Essential Fatty Acids and Osteoarthritis.

OBJECTIVE: Inflammation worsens joint destruction in osteoarthritis (OA) and aggravates pain. Although n-3 fatty acids reduce inflammation, different n-3 fatty acids have different effects on inflammation and clinical outcomes, with eicosapentaenoic acid (EPA) having the strongest effect. We examined whether specific essential fatty acid levels affected the development of OA. METHODS: We studied participants from the Multicenter Osteoarthritis Study (MOST) at risk of developing knee OA. As part of MOST, participants were asked repeatedly about knee pain, and knee radiographs and magnetic resonance images (MRIs) were obtained. Using baseline fasting samples, we analyzed serum fatty acids with standard assays. After excluding participants with baseline OA, we defined two sets of cases based on their status through 60 months' follow-up: those developing incident radiographic OA and those developing incident symptomatic OA (knee pain and radiographic OA). Controls did not develop these outcomes. Additionally, we examined worsening of MRI cartilage damage and synovitis and worsening knee pain and evaluated the number of hand joints affected by nodules. In regression models, we tested the association of each OA outcome with levels of specific n-3 and n-6 fatty acids, adjusting for age, sex, body mass index, education, physical activity, race, baseline pain, smoking, statin use, and depressive symptoms. RESULTS: We studied 363 cases with incident symptomatic knee OA and 295 with incident radiographic knee OA. The mean age was 62 years (59% women). We found no associations of specific n-3 fatty acid levels, including EPA, or of n-6 fatty acid levels with incident OA (eg, for incident symptomatic knee OA, the odds ratio per SD increase in EPA was 1.0 [95% confidence interval 0.87-1.17]). Results for other OA outcomes also failed to suggest a protective effect of specific n-3 fatty acids with OA outcomes. CONCLUSION: We found no association of serum levels of EPA or of other specific n-3 fatty acids or n-6 fatty acids with risk of incident knee OA or other OA outcomes.

Assessing the association of epigenetic age acceleration with osteoarthritis in the Multicenter Osteoarthritis Study (MOST).

PURPOSE: Advancing age is one of the strongest risk factors for osteoarthritis (OA). DNA methylation-based measures of epigenetic age acceleration may provide insights into mechanisms underlying OA. METHODS: We analyzed data from the Multicenter Osteoarthritis Study in a subset of 671 participants ages 45-69 years with no or mild radiographic knee OA. DNA methylation was assessed with the Illumina Infinium MethylationEPIC 850K array. We calculated predicted epigenetic age according to Hannum, Horvath, PhenoAge, and GrimAge epigenetic clocks, then regressed epigenetic age on chronological age to obtain the residuals. Associations between the residuals and knee, hand, and multi-joint OA were assessed using logistic regression, adjusted for chronological age, sex, clinical site, smoking status, and race. RESULTS: Twenty-three percent met criteria for radiographic hand OA, 25% met criteria for radiographic knee OA, and 8% met criteria for multi-joint OA. Mean chronological age (SD) was 58.4 (6.7) years. Mean predicted epigenetic age (SD) according to Horvath, Hannum, PhenoAge, and GrimAge epigenetic clocks was 64.9 (6.4), 68.6 (5.9), 50.5 (7.7), and 67.0 (6.2), respectively. Horvath epigenetic age acceleration was not associated with an increased odds of hand OA, odds ratio (95% confidence intervals) = 1.03 (0.99-1.08), with similar findings for knee and multi-joint OA. We found similar magnitudes of associations for Hannum epigenetic age, PhenoAge, and GrimAge acceleration compared to Horvath epigenetic age acceleration. CONCLUSIONS: Epigenetic age acceleration as measured by various well-validated epigenetic clocks based on DNA methylation was not associated with increased risk of knee, hand, or multi-joint OA independent of chronological age.

Relation of Intra-Articular Mineralization to Knee Pain in Knee Osteoarthritis: A Longitudinal Analysis in the MOST Study.

OBJECTIVE: Intra-articular (IA) calcium crystal deposition is common in knee osteoarthritis (OA), but of unclear significance. It is possible that low-grade, crystal-related inflammation may contribute to knee pain. We examined the longitudinal relation of computed tomography (CT)-detected IA mineralization to the development of knee pain. METHODS: We used data from the National Institutes of Health-funded longitudinal Multicenter Osteoarthritis Study. Participants had knee radiographs and bilateral knee CTs at baseline, and pain assessments every 8 months for 2 years. CT images were scored using the Boston University Calcium Knee Score. We longitudinally examined the relation of CT-detected IA mineralization to the risk of frequent knee pain (FKP), intermittent or constant knee pain worsening, and pain severity worsening using generalized linear mixed-effects models. RESULTS: We included 2,093 participants (mean age 61 years, 57% women, mean body mass index 28.8 kg/m2 ). Overall, 10.2% of knees had IA mineralization. The presence of any IA mineralization in the cartilage was associated with 2.0 times higher odds of having FKP (95% confidence interval [CI] 1.38-2.78) and 1.86 times more frequent intermittent or constant pain (95% CI 1.20-2.78), with similar results seen for the presence of any IA mineralization in the meniscus or joint capsule. A higher burden of IA mineralization anywhere within the knee was associated with a higher odds of all pain outcomes (odds ratio ranged from 2.14 to 2.21). CONCLUSION: CT-detected IA mineralization was associated with risk of having more frequent, persistent, and worsening knee pain over 2 years. Targeting IA mineralization may have therapeutic potential for pain improvement in knee OA.

Magnetic Resonance Imaging-Assessed Subchondral Cysts and Incident Knee Pain and Knee Osteoarthritis: Data From the Multicenter Osteoarthritis Study.

OBJECTIVE: To examine whether knee subchondral cysts, measured on magnetic resonance imaging (MRI), are associated with incident knee osteoarthritis (OA) outcomes. METHODS: We used longitudinal data from the Multicenter Osteoarthritis Study, a community-based cohort of subjects with risk factors for knee OA. Participants without a history of knee surgery and/or inflammatory arthritis (i.e., rheumatoid arthritis and gout) were followed up for 84 months for the following incident outcomes: 1) radiographic knee OA (Kellgren/Lawrence grade ≥2), 2) symptomatic radiographic knee OA (radiographic knee OA and frequent knee pain), and 3) frequent knee pain (with or without radiographic knee OA). In a subset of participants, subchondral cysts were scored on baseline MRIs of 1 knee. Multiple logistic regression, with adjustment for participant characteristics and other baseline knee MRI findings, was used to assess whether subchondral cysts were predictive of incident outcomes. RESULTS: Among the participants with knees eligible for analyses of outcomes over 84 months, incident radiographic knee OA occurred in 22.8% of knees with no baseline radiographic knee OA, symptomatic radiographic knee OA occurred in 17.0% of knees with no baseline symptomatic radiographic knee OA, and frequent knee pain (with or without radiographic knee OA) occurred in 28.8% of knees with no baseline radiographic knee OA and 43.7% of knees with baseline radiographic knee OA. With adjustment for age, sex, and body mass index, the presence of subchondral cysts was not associated with incident radiographic knee OA but was associated with increased odds of incident symptomatic radiographic knee OA (odds ratio 1.92 [95% confidence interval 1.16-3.19]) and increased odds of incident frequent knee pain in those who had radiographic knee OA at baseline (odds ratio 2.11 [95% confidence interval 0.87-5.12]). Stronger and significant associations were observed for outcomes based on consistent reports of frequent knee pain within ~1 month of the study visit. CONCLUSION: Subchondral cysts are likely to be a secondary phenomenon, rather than a primary trigger, of radiographic knee OA, and may predict symptoms in knees with existing disease.

Assessment of bone marrow oedema-like lesions using MRI in patellofemoral knee osteoarthritis: comparison of different MRI pulse sequences.

OBJECTIVE: To compare bone marrow oedema-like lesion (BML) volume in subjects with symptomatic patellofemoral (PF) knee osteoarthritis (OA) using four different MRI sequences and to determine reliability of BML volume assessment using these sequences and their correlation with pain. METHODS: 76 males and females (mean age 55.8 years) with symptomatic patellofemoral knee OA had 1.5 T MRI scans. PD fat suppressed (FS), STIR, contrast-enhanced (CE) T1W FS, and 3D T1W fast field echo (FFE) sequences were obtained. All sequences were assessed by one reader, including repeat assessment of 15 knees using manual segmentation and the measurements were compared. We used random-effects panel linear regression to look for differences in the log-transformed BML volume (due to positive skew in the BML volume distribution) between sequences and to determine associations between BML volumes and knee pain. RESULTS: 58 subjects had PF BMLs present on at least one sequence. Median BML volume measured using T1W FFE sequence was significantly smaller (224.7 mm3, interquartile range [IQR] 82.50-607.95) than the other three sequences. BML volume was greatest on the CE sequence (1129.8 mm3, IQR 467.28-3166.02). Compared to CE sequence, BML volumes were slightly lower when assessed using PDFS (proportional difference = 0.79; 95% confidence interval [CI] 0.62, 1.01) and STIR sequences (proportional difference = 0.85; 95% CI 0.67, 1.08). There were strong correlations between BML volume on PDFS, STIR, and CE T1W FS sequences (ρs = 0.98). Correlations were lower between these three sequences and T1W FFE (ρs = 0.80-0.81). Intraclass correlation coefficients were excellent for proton density fat-suppressed, short-tau inversion recovery, and CE T1W FS sequences (0.991-0.995), while the ICC for T1W FFE was good at 0.88. We found no significant association between BML volumes assessed using any of the sequences and knee pain. CONCLUSION: T1W FFE sequences were less reliable and measured considerably smaller BML volume compared to other sequences. BML volume was larger when assessed using the contrast enhanced T1W FS though not statistically significantly different from BMLs when assessed using PDFS and STIR sequences. ADVANCES IN KNOWLEDGE: This is the first study to assess BMLs by four different MRI pulse sequences on the same data set, including different fluid sensitive sequences and gradient echo type sequence.

Total Serum Testosterone and Western Ontario and McMaster Universities Osteoarthritis Index Pain and Function Among Older Men and Women With Severe Knee Osteoarthritis.

OBJECTIVE: To investigate whether serum total testosterone level is associated with knee pain and function in men and women with severe knee osteoarthritis (OA). METHODS: We enrolled 272 adults age ≥60 years (mean ± SD age 70.4 ± 4.4 years, 53% women) who underwent unilateral total knee replacement (TKR) due to severe knee OA. Serum testosterone levels and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function of the operated and contralateral knee were measured at 6-8 weeks after surgery. At the nonoperated knee, 56% of participants had radiographic knee OA with a Kellgren/Lawrence grade ≥2. Cross-sectional analyses were performed by sex and body mass index (BMI) subgroups, using multivariable regression adjusted for age, physical activity, and BMI. RESULTS: At the operated knee, higher testosterone levels were associated with less WOMAC pain in men (B = -0.62, P = 0.046) and women (B = -3.79, P = 0.02), and less WOMAC disability scores in women (B = -3.62, P = 0.02) and obese men (B = -1.99, P = 0.02). At the nonoperated knee, testosterone levels were not associated with WOMAC pain in men or women, but higher testosterone levels were associated with less disability in women (B = -0.95, P = 0.02). Testosterone levels were inconsistently associated with pain and disability in BMI subgroups among men. Only among obese women, testosterone levels were inversely associated with radiographic knee OA (odds ratio = 0.10, P = 0.003). CONCLUSION: Higher total testosterone levels were associated with less pain in the operated knee in men and women undergoing TKR and less disability in women. At the nonoperated knee, higher testosterone levels were inconsistently associated with less pain and disability.

Efficacy of Computer-Based Telephone Counseling on Long-Term Adherence to Strength Training in Elderly Patients With Knee Osteoarthritis: A Randomized Trial.

OBJECTIVE: To determine whether the Boston Overcoming Osteoarthritis through Strength Training Telephone-Linked Communication (BOOST-TLC) program, a novel telephone-based, motivational, strength-training exercise-adherence counseling intervention, improved adherence to a strength-training exercise program over 2 years. METHODS: Participants were recruited for this 2-year, single-blind, parallel-arm randomized controlled trial from knee osteoarthritis patient registries, community newspapers, and online websites in Massachusetts. Eligibility criteria included age 50 years or older, painful knee osteoarthritis, and ability to use a telephone. Exclusion criteria included medical conditions precluding exercise, inflammatory arthritis, current regular strength training, planned knee replacement surgery, dementia, inability to follow exercise instructions, and inability to use the TLC system. After participating in a group exercise class, participants were randomized to receiving motivational telephone calls through the BOOST-TLC program for 24 months or the control. Both control and intervention participants received a monthly automated phone message reminder to continue the program. Exercise adherence was ascertained by a single self-report item scored 0-10, where 10 represented complete adherence. Outcomes were evaluated at 6, 12, 18, and 24 months. RESULTS: A total of 104 subjects were randomized, and 89 subjects (44 control, 45 TLC) completed the 24-month follow-up. There was no significant difference in adherence at 24 months between groups (mean for control group 4.01 [95% confidence interval (95% CI) 3.03, 4.99], mean for TLC subjects 3.63 [95% CI 2.70, 4.56]; P = 0.57). CONCLUSION: In those with knee osteoarthritis who had participated in an exercise program, frequent motivational telephone reminders did not increase adherence to strength-training exercise.

Step Rate and Worsening of Patellofemoral and Tibiofemoral Joint Osteoarthritis in Women and Men: The Multicenter Osteoarthritis Study.

OBJECTIVE: To determine the association of self-selected walking step rate with worsening of cartilage damage in the patellofemoral (PF) joint and tibiofemoral (TF) joint compartments at a 2-year follow-up visit. METHODS: The Multicenter Osteoarthritis Study (MOST) is a prospective cohort of men and women with or at risk of knee osteoarthritis. Self-selected step rate was measured using an instrumented GAITRite walkway (CIR Systems) at the 60-month visit. Cartilage damage was semiquantitatively graded on magnetic resonance images at the 60- and 84-month visits in the medial and lateral PF and TF compartments. Step rate was divided into quartiles, and logistic regression was used to determine the association of step rate with the risk of worsening cartilage damage in men and women separately. Analyses were adjusted for age, body mass index, and knee injury/surgery. RESULTS: A total of 1,089 participants were included. Mean ± SD age was 66.9 ± 7.5 years, mean ± SD body mass index was 29.6 ± 4.7 kg/m2 , and 62.3% of the participants were women. Women with the lowest step rate had increased risk of lateral PF (risk ratio [RR] 2.1 [95% confidence interval (95% CI) 1.1-3.8]) and TF (RR 1.8 [95% CI 1.1-2.9]) cartilage damage worsening 2 years later compared to those with the highest step rate. Men with the lowest step rate had increased risk of medial TF cartilage damage worsening 2 years later (RR 2.1 [95% CI 1.1-3.9]). CONCLUSION: Lower step rate was associated with increased risk of cartilage damage worsening in the lateral PF and TF compartments in women and worsening medial TF joint damage in men. Future research is necessary to understand the influence of step rate manipulation on joint biomechanics in women and men.

Influence of Antagonistic Hamstring Coactivation on Measurement of Quadriceps Strength in Older Adults.

BACKGROUND: There is limited understanding of how antagonist muscle coactivation relates to measurement of strength in both individuals with and without knee osteoarthritis (KOA). OBJECTIVE: This study sought to determine whether hamstring coactivation during a maximal quadriceps activation task attenuates net quadriceps strength. DESIGN: Cross-sectional cohort analysis was conducted using data from the 60-month visit of the Multicenter Osteoarthritis Study (MOST). SETTING: Laboratory. PARTICIPANTS: A sample of 2328 community-dwelling MOST participants between the ages of 55 and 84 years, with or at elevated risk for KOA, completed the 60-month MOST follow-up visit. Of these, 1666 met inclusion criteria for the current study. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE(S): Quadriceps strength; percentage of combined hamstring coactivation (HC), medial HC, and lateral HC. Quadriceps and hamstring strength were assessed using an isokinetic dynamometer. Surface electromyography was used to assess muscle activation patterns. General linear models, adjusted for age, BMI, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Kellgren-Lawrence (KL) grade and study site, modeled the relationship between antagonist hamstring coactivation and quadriceps strength. RESULTS: Men had significantly greater quadriceps strength (P < .001), history of knee injury (P < .001) and surgery (P = .002), and greater presence of varus malalignment (P < .001). Women had greater pain (P < .001) and proportion of KL grade ≥2 (P = .017). Gender-specific analyses revealed combined HC (P = .013) and lateral HC inversely associated with quadriceps strength in women (P = .023) but not in men (combined HC P = .320, lateral HC P = .755). A nonlinear association was detected between quadriceps strength and medial HC. Assessment of quartiles of medial HC revealed the third quartile had reduced quadriceps strength when compared to the lowest quartile of coactivation in both men and women. CONCLUSIONS: Hamstring coactivation attenuates measured quadriceps strength in women with or at elevated risk for KOA. LEVEL OF EVIDENCE: II.

Mediating Role of Bone Marrow Lesions, Synovitis, Pain Sensitization, and Depressive Symptoms on Knee Pain Improvement Following Substantial Weight Loss.

OBJECTIVE: Massive weight loss leads to marked knee pain reduction in individuals with knee pain, but the reason for the reduction in pain is unknown. This study was undertaken to quantify the contribution of magnetic resonance imaging (MRI)-evidenced changes in pain-sensitive structures, bone marrow lesions (BMLs), and synovitis, and changes in pain sensitization or depressive symptoms, to knee pain improvement after substantial weight loss. METHODS: Morbidly obese patients with knee pain on most days were evaluated before bariatric surgery or medical weight management and at 1-year follow-up for BMLs and synovitis seen on MRI, the pressure pain threshold (PPT) at the patella and the right wrist, depressive symptoms (using the Center for Epidemiologic Studies Depression scale [CES-D]), and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain survey. Natural-effects models were used to quantify the extent that achieving a minimum clinically important difference (MCID) of ≥18% on the WOMAC pain scale could be mediated by weight loss-induced changes in BMLs, synovitis, PPT, and depressive symptoms. RESULTS: Of 75 participants, 53.3% lost ≥20% of weight by 1 year. Of these, 75% attained the MCID for pain improvement, compared with 34.3% in those who had <20% weight loss. Mediation analyses suggested that, in those with at least 20% weight loss, the odds of pain improvement increased by 62%, 15%, and 22% through changes in patella PPT, wrist PPT, and CES-D, respectively, but pain improvement was not mediated by MRI changes in BMLs or synovitis. CONCLUSION: Weight loss-induced knee pain improvement is partially mediated by changes in pain sensitization and depressive symptoms but is independent of MRI changes in BMLs and synovitis.

Effect of Vitamin D supplementation on synovial tissue volume and subchondral bone marrow lesion volume in symptomatic knee osteoarthritis.

BACKGROUND: Data from a recent clinical trial of vitamin D therapy in knee OA suggests that, compared to placebo, vitamin D therapy may be associated with a reduction in effusion-synovitis. Our aim was, using contrast-enhanced (CE) magnetic resonance imaging (MRI), to examine the effect of vitamin D therapy on synovial tissue volume (STV) and also subchondral bone marrow lesion (BML) volume in men and women with symptomatic knee OA. METHODS: Data was acquired from participants who took part in a randomised placebo-controlled trial (UK VIDEO) investigating the effect of vitamin D therapy (800 IU cholecalciferol daily) on radiographic joint space narrowing. A subsample had serial CE MRI scans acquired during the trial. Subjects with serial images were assessed (N = 50) for STV and subchondral BML volume. The difference in the mean change from baseline in these structural outcomes between intervention and placebo groups was assessed using random-effects modelling. RESULTS: The mean age of the 50 subjects (24 active group, 26 placebo group) who contributed data to the analysis was 63.3 years (SD 6.5) and 74% were female. There was no significant difference at 2 years follow-up between the vitamin D and placebo groups in the mean change from baseline for STV (93.9 mm3, 95% CI -1605.0 to 1792.7) and subchondral BML volume (- 313.5 mm3, 95% CI -4244.7 to 3617.7). CONCLUSIONS: Vitamin D supplementation does not appear to have an effect on synovitis or BML volume in patients with symptomatic knee OA. TRIAL REGISTRATION: VIDEO was registered with EudraCT: ref. 2004-000169-37. The protocol for the trial can be accessed at https://www.ctu.mrc.ac.uk/studies/all-studies/v/video/.

Weight loss changed gait kinematics in individuals with obesity and knee pain.

BACKGROUND: Obesity is a mechanical risk factor for osteoarthritis. In individuals with obesity, knee joint pain is prevalent. Weight loss reduces joint loads, and therefore potentially delays disease progression; however, how the knee joint responds to weight loss in individuals with obesity and knee pain is not clear. RESEARCH QUESTION: To assess the effect of weight loss on knee joint kinematics during gait in individuals with obesity and knee pain. METHODS: We recruited individuals with obesity (BMI ≥ 35) and knee pain who were participating in a weight loss program which included bariatric surgery or medical management. At baseline and 1 year follow-up, participants walked on a treadmill, and their knee joint kinematics were assessed using a dual-fluoroscopic imaging system and subject-specific magnetic resonance imaging knee joint models. Gait changes were represented by change in range of tibiofemoral motion, i.e., excursions in flexion-extension, adduction-abduction, internal-external rotation, anterior-posterior translation, medial-lateral translation, and superior-inferior translation during gait. RESULTS: Twelve individuals with obesity and knee pain completed the gait analysis at baseline and 1 year follow-up. Participants lost on average 10.4% (standard deviation: 17.2%) of their baseline body weight. Reduction in body weight was associated with increased range of flexion-extension (r = -0.75, p < 0.01) and decreased range of adduction-abduction (r = 0.60, p = 0.04) during gait. The reduction in body weight was also associated with self-reported pain decrease (r = 0.62, p = 0.04); however, the change in pain was not significantly associated with kinematic changes. SIGNIFICANCE: Weight loss was associated with improved gait kinematics in the sagittal and frontal planes. The change in gait pattern in individuals with obesity and knee pain was not associated with the change in pain given a reduction in body weight.

Association of Back Pain with All-Cause and Cause-Specific Mortality Among Older Women: a Cohort Study.

BACKGROUND: The impact of back pain on disability in older women is well-understood, but the influence of back pain on mortality is unclear. OBJECTIVE: To examine whether back pain was associated with all-cause and cause-specific mortality in older women and mediation of this association by disability. DESIGN: Prospective cohort study. SETTING: The Study of Osteoporotic Fractures. PARTICIPANTS: Women aged 65 or older. MEASUREMENT: Our primary outcome, time to death, was assessed using all-cause and cause-specific adjusted Cox models. We used a four-category back pain exposure (no back pain, non-persistent, infrequent persistent, or frequent persistent back pain) that combined back pain frequency and persistence across baseline (1986-1988) and first follow-up (1989-1990) interviews. Disability measures (limitations of instrumental activities of daily living [IADL], slow chair stand time, and slow walking speed) from 1991 were considered a priori potential mediators. RESULTS: Of 8321 women (mean age 71.5, SD = 5.1), 4975 (56%) died over a median follow-up of 14.1 years. A higher proportion of women with frequent persistent back pain died (65.8%) than those with no back pain (53.5%). In the fully adjusted model, women with frequent persistent back pain had higher hazard of all-cause (hazard ratio [HR] = 1.24 [95% CI, 1.11-1.39]), cardiovascular (HR = 1.34 [CI, 1.12-1.62]), and cancer (HR = 1.33, [CI 1.03-1.71]) mortality. No association with mortality was observed for other back pain categories. In mediation analyses, IADL limitations explained 47% of the effect of persistent frequent back pain on all-cause mortality, slow chair stand time, and walking speed, explained 27% and 24% (all significant, p < 0.001), respectively. LIMITATIONS: Only white women were included. CONCLUSION: Frequent persistent back pain was associated with increased mortality in older women. Much of this association was mediated by disability.

Mechanisms of Osteoarthritis (OA) Pain.

PURPOSE OF REVIEW: Osteoarthritis (OA) is a major cause of pain and disability worldwide. There is, however, a relatively poor correlation between the severity of OA based on plain radiograph changes and symptoms. In this review, we consider the mechanisms of pain in OA. RECENT FINDINGS: It is now widely recognised that OA is a disease of the whole joint. Data from large observational studies which have used magnetic resonance imaging (MRI) suggest that pain in OA is associated with a number of structural factors including the presence of bone marrow lesions (BMLs) and also synovitis. There is evidence also of alterations in nerve processing and that both peripheral and central nerve sensitisation may contribute to pain in OA. Identification of the causes of pain in an individual patient may be of benefit in helping to better target with appropriate therapy to help reduce their symptoms and improve function.

Changes in Pain Sensitization After Bariatric Surgery.

OBJECTIVE: To evaluate changes in pain (at the knee and elsewhere) and pain sensitization in obese subjects with knee pain who were having bariatric surgery compared with similarly obese individuals who were undergoing medical management. METHODS: This study included a cohort of subjects who were having bariatric surgery and those undergoing medical management. Knee pain severity of the more painful knee (index knee) was assessed at baseline and at 12 months using the Western Ontario and McMaster Universities Osteoarthritis Index. The pressure pain threshold (PPT) was evaluated at the index patella and the right wrist. Low patella PPT may reflect peripheral and/or central sensitization, and low wrist PPT may reflect central sensitization. The mean change in measures of pain and pain sensitization was analyzed in the surgery and medical management groups separately. RESULTS: A total of 45 subjects in the surgery group and 22 in the medical management group completed baseline and follow-up visits. The mean weight loss was 32.7 kg (29.0%) and 4.6 kg (4.1%) in the surgery and medical management groups, respectively. Knee pain decreased only in the surgery group, in which the PPT at the patella improved by 38.5% (P = 0.0007) and at the wrist by 30.9% (P = 0.005). There was no significant change in PPT in the medical management group. CONCLUSION: Persons who underwent bariatric surgery experienced an improvement in pain sensitization, reflected by improvements in PPT. This improvement was observed not only at the patella, but also at the wrist, suggesting that central sensitization improved after bariatric surgery.

Bone marrow lesions in osteoarthritis: What lies beneath.

Osteoarthritis (OA) is the most common joint disease in the United States, affecting more than 30 million people, and is characterized by cartilage degeneration in articulating joints. OA can be viewed as a group of overlapping disorders, which result in functional joint failure. However, the precise cellular and molecular events within which lead to these clinically observable changes are neither well understood nor easily measurable. It is now clear that multiple factors, in multiple joint tissues, contribute to degeneration. Changes in subchondral bone are recognized as a hallmark of OA, but are normally associated with late-stage disease when degeneration is well established. However, early changes such as Bone Marrow Lesions (BMLs) in OA are a relatively recent discovery. BMLs are patterns from magnetic resonance images (MRI) that have been linked with pain and cartilage degeneration. Their potential utility in predicting progression, or as a target for therapy, is not yet fully understood. Here, we will review the current state-of-the-art in this field under three broad headings: (i) BMLs in symptomatic OA: malalignment, joint pain, and disease progression; (ii) biological considerations for bone-cartilage crosstalk in joint disease; and (iii) mechanical factors that may underlie BMLs and drive their communication with other joint tissues. Thus, this review will provide insights on this topic from a clinical, biological, and mechanical perspective. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1818-1825, 2018.

Genome-wide association and functional studies identify a role for matrix Gla protein in osteoarthritis of the hand.

OBJECTIVE: Osteoarthritis (OA) is the most common form of arthritis and the leading cause of disability in the elderly. Of all the joints, genetic predisposition is strongest for OA of the hand; however, only few genetic risk loci for hand OA have been identified. Our aim was to identify novel genes associated with hand OA and examine the underlying mechanism. METHODS: We performed a genome-wide association study of a quantitative measure of hand OA in 12 784 individuals (discovery: 8743, replication: 4011). Genome-wide significant signals were followed up by analysing gene and allele-specific expression in a RNA sequencing dataset (n=96) of human articular cartilage. RESULTS: We found two significantly associated loci in the discovery set: at chr12 (p=3.5 × 10-10) near the matrix Gla protein (MGP) gene and at chr12 (p=6.1×10-9) near the CCDC91 gene. The DNA variant near the MGP gene was validated in three additional studies, which resulted in a highly significant association between the MGP variant and hand OA (rs4764133, Betameta=0.83, Pmeta=1.8*10-15). This variant is high linkage disequilibrium with a coding variant in MGP, a vitamin K-dependent inhibitor of cartilage calcification. Using RNA sequencing data from human primary cartilage tissue (n=96), we observed that the MGP RNA expression of the hand OA risk allele was significantly lowercompared with the MGP RNA expression of the reference allele (40.7%, p<5*10-16). CONCLUSIONS: Our results indicate that the association between the MGP variant and increased risk for hand OA is caused by a lower expression of MGP, which may increase the burden of hand OA by decreased inhibition of cartilage calcification.

Dietary Fiber Intake in Relation to Knee Pain Trajectory.

OBJECTIVE: Dietary fiber may reduce knee pain, in part by lowering body weight and reducing inflammation. In this study, we assessed whether fiber intake was associated with patterns of knee pain development. METHODS: In a prospective, multicenter cohort of 4,796 men and women ages 45-79 years with or at risk of knee osteoarthritis, participants underwent annual followups for 8 years. Dietary fiber intake was estimated using a validated food frequency questionnaire at baseline. Group-based trajectory modeling was used to identify Western Ontario and McMaster Universities Osteoarthritis Index pain trajectories, which were assessed for associations with dietary fiber intake using polytomous regression models. RESULTS: Of the eligible participants (4,470 persons and 8,940 knees, mean ± SD age 61.3 ± 9.1 years, 58% women), 4.9% underwent knee replacement and were censored at the time of surgery. Four distinct knee pain patterns were identified: no pain (34.5%), mild pain (38.1%), moderate pain (21.2%), and severe pain (6.2%). Dietary total fiber was inversely related to membership in the moderate or severe pain groups (P ≤ 0.006 for trend for both). Subjects in the highest versus those in the lowest quartile of total fiber intake had a lower risk of belonging to the moderate pain pattern group (odds ratio [OR] 0.76 [95% confidence interval (95% CI) 0.61-0.93]) and severe pain pattern group (OR 0.56 [95% CI 0.41-0.78]). Similar results were found with grain fiber and these 2 pain pattern groups. CONCLUSION: Our findings suggest that a high intake of dietary total or grain fiber, particularly the recommended daily fiber average intake of 25 gm per day, is associated with a lower risk of developing moderate or severe knee pain over time.

Structural effects of sprifermin in knee osteoarthritis: a post-hoc analysis on cartilage and non-cartilaginous tissue alterations in a randomized controlled trial.

BACKGROUND: A recent publication on efficacy of Sprifermin for knee osteoarthritis (OA) using quantitatively MRI-defined central medial tibio-femoral compartment cartilage thickness as the structural primary endpoint reported no statistically significant dose response. However, Sprifermin was associated with statistically significant, dose-dependent reductions in loss of total and lateral tibio-femoral cartilage thickness. Based on these preliminary promising data a post-hoc analysis of secondary assessment and endpoints was performed to evaluate potential effects of Sprifermin on semi-quantitatively evaluated structural MRI parameters. Aim of the present analysis was to determine effects of sprifermin on several knee joint tissues over a 12 month period. METHODS: 1.5 T or 3 T MRIs were acquired at baseline and 12 months follow-up using a standard protocol. MRIs were read according to the Whole-Organ Magnetic Resonance Imaging Score (WORMS) scoring system (in 14 articular subregions) by four muskuloskeletal radiologists independently. Analyses focused on semiquantitative changes in the 100 µg subgroup and matching placebo of multiple MRI-defined structural alterations. Analyses included a delta-subregional and delta-sum approach for the whole knee and the medial and lateral tibio-femoral (MTFJ, LTFJ), and patello-femoral (PFJ) compartments, taking into account number of subregions showing no change, improvement or worsening and changes in the sum of subregional scores. Mann-Whitney - Wilcoxon tests assessed differences between groups. RESULTS: Fifty-seven and 18 patients were included in the treatment and matched placebo subgroups. Less worsening of cartilage damage was observed from baseline to 12 months in the PFJ (0.02, 95 % confidence interval (CI) (-0.04, 0.08) vs. placebo 0.22, 95 % CI (-0.05, 0.49), p = 0.046). For bone marrow lesions (BMLs), more improvement was observed from 6 to 12 months for whole knee analyses (-0.14, 95 % CI (-0.48, 0.19) vs. placebo 0.44, 95 % CI (-0.15, 1.04), p = 0.042) although no significant effects were seen from the baseline visit, or in Hoffa-synovitis, effusion-synovitis, menisci and osteophytes. CONCLUSIONS: In this post-hoc analysis cartilage showed less worsening from baseline to 12 months in the PFJ, and BMLs showed more improvement from 6 to 12 months for the whole knee. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01033994 .