A maternal brain hormone that builds bone.

In lactating mothers, the high calcium (Ca2+) demand for milk production triggers significant bone loss1. Although oestrogen normally counteracts excessive bone resorption by promoting bone formation, this sex steroid drops precipitously during this postpartum period. Here we report that brain-derived cellular communication network factor 3 (CCN3) secreted from KISS1 neurons of the arcuate nucleus (ARCKISS1) fills this void and functions as a potent osteoanabolic factor to build bone in lactating females. We began by showing that our previously reported female-specific, dense bone phenotype2 originates from a humoral factor that promotes bone mass and acts on skeletal stem cells to increase their frequency and osteochondrogenic potential. This circulatory factor was then identified as CCN3, a brain-derived hormone from ARCKISS1 neurons that is able to stimulate mouse and human skeletal stem cell activity, increase bone remodelling and accelerate fracture repair in young and old mice of both sexes. The role of CCN3 in normal female physiology was revealed after detecting a burst of CCN3 expression in ARCKISS1 neurons coincident with lactation. After reducing CCN3 in ARCKISS1 neurons, lactating mothers lost bone and failed to sustain their progeny when challenged with a low-calcium diet. Our findings establish CCN3 as a potentially new therapeutic osteoanabolic hormone for both sexes and define a new maternal brain hormone for ensuring species survival in mammals.

Chemokine CXCL9, a marker of inflammaging, is associated with changes of muscle strength and mortality in older men.

Our study examined associations of the CXC motif chemokine ligand 9 (CXCL9), a pro-inflammatory protein implicated in age-related inflammation, with musculoskeletal function in elderly men. We found in certain outcomes both cross-sectional and longitudinal significant associations of CXCL9 with poorer musculoskeletal function and increased mortality in older men. This requires further investigation. PURPOSE: We aim to determine the relationship of (CXCL9), a pro-inflammatory protein implicated in age-related inflammation, with both cross-sectional and longitudinal musculoskeletal outcomes and mortality in older men. METHODS: A random sample from the Osteoporotic Fractures in Men (MrOS) Study cohort (N = 300) was chosen for study subjects that had attended the third and fourth clinic visits, and data was available for major musculoskeletal outcomes (6 m walking speed, chair stands), hip bone mineral density (BMD), major osteoporotic fracture, mortality, and serum inflammatory markers. Serum levels of CXCL9 were measured by ELISA, and the associations with musculoskeletal outcomes were assessed by linear regression and fractures and mortality with Cox proportional hazards models. RESULTS: The mean CXCL9 level of study participants (79.1 ± 5.3 years) was 196.9 ± 135.2 pg/ml. There were significant differences for 6 m walking speed, chair stands, physical activity scores, and history of falls in the past year across the quartiles of CXCL9. However, higher CXCL9 was only significantly associated with changes in chair stands (ß = - 1.098, p < 0.001) even after adjustment for multiple covariates. No significant associations were observed between CXCL9 and major osteoporotic fracture or hip BMD changes. The risk of mortality increased with increasing CXCL9 (hazard ratio quartile (Q)4 vs Q1 1.98, 95% confidence interval 1.25-3.14; p for trend < 0.001). CONCLUSIONS: Greater serum levels of CXCL9 were significantly associated with a decline in chair stands and increased mortality. Additional studies with a larger sample size are needed to confirm our findings.

Predictive value of sarcopenia components for all-cause mortality: findings from population-based cohorts.

BACKGROUND: Low grip strength and gait speed are associated with mortality. However, investigation of the additional mortality risk explained by these measures, over and above other factors, is limited. AIM: We examined whether grip strength and gait speed improve discriminative capacity for mortality over and above more readily obtainable clinical risk factors. METHODS: Participants from the Health, Aging and Body Composition Study, Osteoporotic Fractures in Men Study, and the Hertfordshire Cohort Study were analysed. Appendicular lean mass (ALM) was ascertained using DXA; muscle strength by grip dynamometry; and usual gait speed over 2.4-6 m. Verified deaths were recorded. Associations between sarcopenia components and mortality were examined using Cox regression with cohort as a random effect; discriminative capacity was assessed using Harrell's Concordance Index (C-index). RESULTS: Mean (SD) age of participants (n = 8362) was 73.8(5.1) years; 5231(62.6%) died during a median follow-up time of 13.3 years. Grip strength (hazard ratio (95% CI) per SD decrease: 1.14 (1.10,1.19)) and gait speed (1.21 (1.17,1.26)), but not ALM index (1.01 (0.95,1.06)), were associated with mortality in mutually-adjusted models after accounting for age, sex, BMI, smoking status, alcohol consumption, physical activity, ethnicity, education, history of fractures and falls, femoral neck bone mineral density (BMD), self-rated health, cognitive function and number of comorbidities. However, a model containing only age and sex as exposures gave a C-index (95% CI) of 0.65(0.64,0.66), which only increased to 0.67(0.67,0.68) after inclusion of grip strength and gait speed. CONCLUSIONS: Grip strength and gait speed may generate only modest adjunctive risk information for mortality compared with other more readily obtainable risk factors.

Clinical and imaging findings associated with preservation of knee joint health over 8 years in individuals aged 65 and over: data from the OAI.

OBJECTIVE: While risk factors for osteoarthritis (OA) are well known, it is not well understood why certain individuals maintain high mobility and joint health throughout their life while others demonstrate OA at older ages. The purpose of this study was to assess which demographic, clinical and MRI quantitative and semi-quantitative factors are associated with preserving healthy knees in older individuals. METHODS: This study analyzed data from the OA Initiative (OAI) cohort of individuals at the age of 65 years or above. Participants without OA at baseline (BL) (Kellgren-Lawrence (KL) ≤ 1) were followed and classified as incident cases (KL ≥ 2 during follow-up; n = 115) and as non-incident (KL ≤ 1 over 96-month; n = 391). Associations between the predictor-variables sex, age, BMI, race, clinical scoring systems, T2 relaxation times and Whole-Organ Magnetic Resonance Imaging-Score (WORMS) readings at BL and the preservation of healthy knees (KL ≤ 1) during a 96-month follow-up period were assessed using logistic regression models. RESULTS: Obesity and presence of pain showed a significant inverse association with maintaining radiographically normal joints in patients aged 65 and above. T2 relaxation times of the lateral femur and tibia as well as the medial femur were also significantly associated with maintaining radiographically normal knee joints. Additionally, absence of lesions of the lateral meniscus and absence of cartilage lesions in the medial and patellofemoral compartments were significantly associated with maintaining healthy knee joints. CONCLUSION: Overall, this study provides protective clinical parameters as well as quantitative and semi-quantitative MR-imaging parameters associated with maintaining radiographically normal knee joints in an older population over 8 years.

Effect of weight loss on knee joint synovitis over 48 months and mediation by subcutaneous fat around the knee: data from the Osteoarthritis Initiative.

BACKGROUND: Obesity influences the development of osteoarthritis via low-grade inflammation. Progression of local inflammation (= synovitis) increased with weight gain in overweight and obese women compared to stable weight. Synovitis could be associated with subcutaneous fat (SCF) around the knee. Purpose of the study was to investigate the effect of weight loss on synovitis progression and to assess whether SCF around the knee mediates the relationship between weight loss and synovitis progression. METHODS: We included 234 overweight and obese participants (body mass index [BMI] ≥ 25 kg/m2) from the Osteoarthritis Initiative (OAI) with > 10% weight loss (n = 117) or stable overweight (< ± 3% change, n = 117) over 48 months matched for age and sex. In magnetic resonance imaging (MRI) at baseline and 48 months, effusion-synovitis and Hoffa-synovitis using the MRI Osteoarthritis Knee Score (MOAKS) and average joint-adjacent SCF (ajSCF) were assessed. Odds-ratios (ORs) for synovitis progression over 48 months (≥ 1 score increase) were calculated in logistic regression models adjusting for age, sex, baseline BMI, Physical Activity Scale for the Elderly (PASE), and baseline SCF measurements. Mediation of the effect of weight loss on synovitis progression by local SCF change was assessed. RESULTS: Odds for effusion-synovitis progression decreased with weight loss and ajSCF decrease (odds ratio [OR] = 0.61 and 0.56 per standard deviation [SD] change, 95% confidence interval [CI] 0.44, 0.83 and 0.40, 0.79, p = 0.002 and 0.001, respectively), whereas odds for Hoffa-synovitis progression increased with weight loss and ajSCF decrease (OR = 1.47 and 1.48, CI 1.05, 2.04 and 1.02, 2.13, p = 0.024 and 0.038, respectively). AjSCF decrease mediated 39% of the effect of weight loss on effusion-synovitis progression. CONCLUSIONS: Effusion-synovitis progression was slowed by weight loss and decrease in local subcutaneous fat. Hoffa-synovitis characterized by fluid in the infrapatellar fat pad increased at the same time, suggesting a decreasing fat pad rather than active synovitis. Decrease in local subcutaneous fat partially mediated the systemic effect of weight loss on synovitis.

Interactions of Nonsteroidal Antiinflammatory Drugs and Aspirin and Risk of Cardiovascular Disease in Patients With Osteoarthritis.

Nonsteroidal antiinf lammatory drugs (NSAIDs) remain the mainstay of the pharmacologic management for relieving osteoarthritis pain, and low-dose aspirin is often prescribed to osteoarthritis patients who are at high risk of cardiovascular disease (CVD). We conducted cohort studies using data from The Health Improvement Network (THIN) database (2000-2019) to assess whether the relationship of initiation of naproxen or ibuprofen vs. initiation of other NSAIDs (excluding both naproxen and ibuprofen), respectively, to the risk of CVD was modified by coprescription of low-dose aspirin among the participants with osteoarthritis. Among participants without coprescription of aspirin, the risk of CVD was lower in naproxen initiators (10.3/1000 person-years) than in other NSAIDs initiators (13.2/1000 person-years; hazard ratio = 0.71, 95% confidence interval: 0.60, 0.85). Among participants with coprescription of aspirin, however, the risk of CVD was higher among naproxen initiators (36.9/1000 person-years) than that among other NSAIDs initiators (34.8/1000 person-years; hazard ratio = 1.48, 95% confidence interval: 1.12, 1.84). The association was significantly modified by coprescription of aspirin (P < 0.001). Similar findings were observed in the association of initiation of ibuprofen vs. other NSAIDs with the risk of CVD, which was significantly modified by coprescription of aspirin (P < 0.001). These findings suggest that osteoarthritis patients and clinicians should be aware of the potential CVD risk of concurrently taking naproxen or ibuprofen and low-dose aspirin.

Associations between weight change, knee subcutaneous fat and cartilage thickness in overweight and obese individuals: 4-Year data from the osteoarthritis initiative.

OBJECTIVE: To assess (i) the impact of changes in body weight on changes in joint-adjacent subcutaneous fat (SCF) and cartilage thickness over 4 years and (ii) the relation between changes in joint-adjacent SCF and knee cartilage thickness. DESIGN: Individuals from the Osteoarthritis Initiative (total=399) with > 10% weight gain (n=100) and > 10% weight loss (n=100) over 4 years were compared to a matched control cohort with less than 3% change in weight (n=199). 3.0T Magnetic Resonance Imaging (MRI) of the right knee was performed at baseline and after 4 years to quantify joint-adjacent SCF and cartilage thickness. Linear regression models were used to evaluate the associations between the (i) weight change group and 4-year changes in both knee SCF and cartilage thickness, and (ii) 4-year changes in knee SCF and in cartilage thickness. Analyses were adjusted for age, sex, baseline body mass index (BMI), tibial diameter (and weight change group in analysis (ii)). RESULTS: Individuals who lost weight over 4-years had significantly less joint-adjacent SCF (beta range, medial/lateral joint sides: 2.2-4.2 mm, p < 0.001) than controls; individuals who gained weight had significantly greater joint-adjacent SCF than controls (beta range: -1.4 to -3.9 mm, p < 0.001). No statistically significant associations were found between weight change and cartilage thickness change. However, increases in joint-adjacent SCF over 4 years were significantly associated with decreases in cartilage thickness (p = 0.04). CONCLUSIONS: Weight change was associated with joint-adjacent SCF, but not with change in cartilage thickness. However, 4-year increases in joint-adjacent SCF were associated with decreases in cartilage thickness independent of baseline BMI and weight change group.

Chronic arthritides and bone structure: focus on rheumatoid arthritis-an update.

Normal bone remodeling depends of a balance between bone forming cells, osteoblasts and bone resorbing cells, the osteoclasts. In chronic arthritides and some inflammatory and autoimmune diseases such as rheumatoid arthritis, there is a great constellation of cytokines produced by pannus that impair bone formation and stimulate bone resorption by inducing osteoclast differentiation and inhibiting osteoblast maturation. Patients with chronic inflammation have multiple causes that lead to low bone mineral density, osteoporosis and a high risk of fracture including circulating cytokines, impaired mobility, chronic administration of glucocorticoids, low vitamin D levels and post-menopausal status in women, among others. Biologic agents and other therapeutic measures to reach prompt remission might ameliorate these deleterious effects. In many cases, bone acting agents need to be added to conventional treatment to reduce the risk of fractures and to preserve articular integrity and independency for daily living activities. A limited number of studies related to fractures in chronic arthritides were published, and future investigation is needed to determine the risk of fractures and the protective effects of different treatments to reduce this risk.

The effect of interactions between BMI and sustained depressive symptoms on knee osteoarthritis over 4 years: data from the osteoarthritis initiative.

BACKGROUND: To assess the compound effects of BMI and sustained depressive symptoms on changes in knee structure, cartilage composition, and knee pain over 4 years using statistical interaction analyses. METHODS: One thousand eight hundred forty-four individuals from the Osteoarthritis Initiative Database were analyzed at baseline and 4-year follow-up. Individuals were categorized according to their BMI and presence of depressive symptoms (based on the Center for Epidemiological Studies Depression Scale (threshold≥16)) at baseline and 4-year follow-up. 3 T MRI was used to quantify knee cartilage T2 over 4 years, while radiographs were used to assess joint space narrowing (JSN). Mixed effects models examined the effect of BMI-depressive symptoms interactions on outcomes of cartilage T2, JSN, and knee pain over 4-years. RESULTS: The BMI-depressive symptoms interaction was significantly associated with knee pain (p < 0.001) changes over 4 years, but not with changes in cartilage T2 (p = 0.27). In women, the BMI-depressive symptoms interaction was significantly associated with JSN (p = 0.01). In a group-based analysis, participants with obesity and depression had significantly greater 4-year changes in knee pain (coeff.(obesity + depression vs. no_obesity + no_depression) = 4.09, 95%CI = 3.60-4.58, p < 0.001), JSN (coeff. = 0.60, 95%CI = 0.44-0.77, p < 0.001), and cartilage T2 (coeff. = 1.09, 95%CI = 0.68-1.49, p < 0.001) than participants without depression and normal BMI. CONCLUSIONS: The compound effects of obesity and depression have greater impact on knee pain and JSN progression compared to what would be expected based on their individual effects.

Validation of a Semiautomatic Image Analysis Software for the Quantification of Musculoskeletal Tissues.

Accurate quantification of bone, muscle, and their components is still an unmet need in the musculoskeletal field. Current methods to quantify tissue volumes in 3D images are expensive, labor-intensive, and time-consuming; thus, a reliable, valid, and quick application is highly needed. Tissue Compass is a standalone software for semiautomatic segmentation and automatic quantification of musculoskeletal organs. To validate the software, cross-sectional micro-CT scans images of rat femur (n = 19), and CT images of hip and abdomen (n = 100) from the Osteoporotic Fractures in Men (MrOS) Study were used to quantify bone, hematopoietic marrow (HBM), and marrow adipose tissue (MAT) using commercial manual software as a comparator. Also, abdominal CT scans (n = 100) were used to quantify psoas muscle volumes and intermuscular adipose tissue (IMAT) using the same software. We calculated Pearson's correlation coefficients, individual intra-class correlation coefficients (ICC), and Bland-Altman limits of agreement together with Bland-Altman plots to show the inter- and intra-observer agreement between Tissue Compass and commercially available software. In the animal study, the agreement between Tissue Compass and commercial software was r > 0.93 and ICC > 0.93 for rat femur measurements. Bland-Altman limits of agreement was - 720.89 (- 1.5e+04, 13,074.00) for MAT, 4421.11 (- 1.8e+04, 27,149.73) for HBM and - 6073.32 (- 2.9e+04, 16,388.37) for bone. The inter-observer agreement for QCT human study between two observers was r > 0.99 and ICC > 0.99. Bland-Altman limits of agreement was 0.01 (- 0.07, 0.10) for MAT in hip, 0.02 (- 0.08, 0.12) for HBM in hip, 0.05 (- 0.15, 0.25) for bone in hip, 0.02 (- 0.18, 0.22) for MAT in L1, 0.00 (- 0.16, 0.16) for HBM in L1, and 0.02 (- 0.23, 0.27) for bone in L1. The intra-observer agreement for QCT human study between the two applications was r > 0.997 and ICC > 0.99. Bland-Altman limits of agreement was 0.03 (- 0.13, 0.20) for MAT in hip, 0.05 (- 0.08, 0.18) for HBM in hip, 0.05 (- 0.24, 0.34) for bone in hip, - 0.02 (- 0.34, 0.31) for MAT in L1, - 0.14 (- 0.44, 0.17) for HBM in L1, - 0.29 (- 0.62, 0.05) for bone in L1, 0.03 (- 0.08, 0.15) for IMAT in psoas, and 0.02 (- 0.35, 0.38) for muscle in psoas. Compared to a conventional application, Tissue Compass demonstrated high accuracy and non-inferiority while also facilitating easier analyses. Tissue Compass could become the tool of choice to diagnose tissue loss/gain syndromes in the future by requiring a small number of CT sections to detect tissue volumes and fat infiltration.

Slower upper extremity function in older adults with hyperkyphosis negatively impacts the 6-min walk test.

BACKGROUND: Approximately 30% to 40% of older adults have hyperkyphosis, defined as excessive curvature of the thoracic spine. Hyperkyphosis is associated with increased morbidity and mortality. This study aimed to determine whether hyperkyphosis (Cobb's angle) and upper extremity tasks were independently associated with the 6-min walk test (6MWT) in community-dwelling older adults with hyperkyphosis. METHODS: In this cross-sectional study, we studied 71 women and 28 men aged 60-87 from the study of hyperkyphosis, exercise, and function trial (SHEAF) who had kyphosis, 3 timed upper extremity tasks and the 6MWT assessed at their baseline visit. We used standing lateral spine radiographs and a standardized protocol for thoracic kyphosis (T4-T12) to measure Cobb angle of kyphosis. In addition, 3 activity of daily living (ADL) extremity tests (putting on and removing a laboratory coat, picking up a penny from the floor, and lifting a 7-lb. book to a shelf) were used. RESULTS: The mean ± SD age was 70.1 ± 6.1 years. The mean ± SD Cobb angle of kyphosis was 57.4 ± 12.5 degrees. On average ± SD, the participants walked 504.8 ± 84.2 m in 6 min and took 2.4 ± 2.2 prescription medications. The mean ± SD height was 164.7 ± 8.5 cm, weight was 68.7 ± 13.1 kg, and BMI was 25.2 ± 4.0 kg/m2. Multivariate regression revealed that age, height, upper extremity book lift task, and the number of prescribed medications were significant predictors of performance on the 6MWT (p < 0.05). CONCLUSIONS: While kyphosis was not associated with the 6MWT, timed tests of upper extremity function indicated that upper body dynamics can affect walking performance. In addition, sociodemographic factors and the number of prescribed medications were significant contributing factors to the 6MWT in older adults with mild to moderate hyperkyphosis. These results illustrate multifactorial influences on physical performance and the need for an integrated and targeted approach in helping older hyperkyphotic adults maintain healthy physical functioning as they age.

Oxylipins Associated with D3-Creatine Muscle Mass/Weight and Physical Performance among Community-Dwelling Older Men.

Poor physical function is highly prevalent with aging, and strongly associated with D3-creatine muscle mass/weight. Using metabolomics, we previously identified several triglycerides consisting mostly of polyunsaturated fatty acids that were higher in older adults with good mobility. Here, we sought to further investigate polyunsaturated fatty-acid-related metabolites, i.e., oxylipins, and their associations with D3-creatine muscle mass/weight, gait speed, grip strength, and the Short Physical Performance Battery among 463 older men from the Osteoporotic Fractures in Men Study (MrOS). Oxylipins were measured in fasting serum using liquid chromatography-mass spectrometry. Muscle mass was estimated using D3-creatine dilution and adjusted for body size. We used linear regression to determine oxylipins associated with D3-creatine muscle mass/weight and physical performance, while adjusting for age, education, physical activity, Western dietary pattern, fish oil supplementation, and multiple comparisons. Among 42 oxylipins, none were associated with grip strength and 3 were associated with the Short Physical Performance Battery. In contrast, 18 and 17 oxylipins were associated with D3-creatine muscle mass/weight and gait speed, respectively. A subset of associations between oxylipins and gait speed were partially attenuated by D3-creatine muscle mass/weight. Higher levels of fatty acid alcohol and ketone oxylipins tended to be most strongly associated with gait speed and D3-creatine muscle mass/weight, potentially reflecting anti-inflammatory activity from these select oxylipins in MrOS older men.

Factors associated with the 6-minute walk test performance in older adults with hyperkyphosis.

Age-related hyperkyphosis is associated with adverse health outcomes, such as falls, fractures, and mortality. However, few studies investigated the relationship between the severity of hyperkyphosis and physical endurance in older adults. This study examined whether a degree of hyperkyphosis curvature was independently associated with the 6-minute walk test (6MWT) distance. We analyzed the baseline data of 112 older adults aged 60-92 enrolled in the Specialized Center of Research (SCOR) Kyphosis trial. The majority of the sample had at least a college degree and were white. On average, participants walked 503.9 (SD 82.3) meters in 6 minutes. Multivariate regression results showed that the degree of hyperkyphosis curvature was not independently associated with the 6MWT distance, but taller height, lighter weight, and less prescription medication were significant predictors of better performance on the 6MWT distance. Validation of the study findings in a large, diverse older adult population is warranted.

Molecular pharming to support human life on the moon, mars, and beyond.

Space missions have always assumed that the risk of spacecraft malfunction far outweighs the risk of human system failure. This assumption breaks down for longer duration exploration missions and exposes vulnerabilities in space medical systems. Space agencies can no longer reduce the majority of the human health and performance risks through crew members selection process and emergency re-supply or evacuation. No mature medical solutions exist to address this risk. With recent advances in biotechnology, there is promise for lessening this risk by augmenting a space pharmacy with a biologically-based space foundry for the on-demand manufacturing of high-value medical products. Here we review the challenges and opportunities of molecular pharming, the production of pharmaceuticals in plants, as the basis of a space medical foundry to close the risk gap in current space medical systems. Plants have long been considered to be an important life support object in space and can now also be viewed as programmable factories in space. Advances in molecular pharming-based space foundries will have widespread applications in promoting simple and accessible pharmaceutical manufacturing on Earth.

Joint-adjacent Adipose Tissue by MRI is Associated With Prevalence and Progression of Knee Degenerative Changes: Data from the Osteoarthritis Initiative.

BACKGROUND: Adipose tissue has recently gained interest as an independent imaging biomarker for osteoarthritis. PURPOSE: To explore 1) cross-sectional associations between local subcutaneous fat (SCF) thickness at the knee and the extent of degenerative changes in overweight and obese individuals and 2) associations between local fat distribution and progression of osteoarthritis over 4 years. STUDY TYPE: Retrospective cohort study. POPULATION: 338 obese and overweight participants from the Osteoarthritis Initiative cohort without radiographic evidence of osteoarthritis. FIELD STRENGTH: 3T: 3D-FLASH-WE; 3D-DESS-WE; T1w-SE; MSME. ASSESSMENT: Baseline SCF thickness was measured in standardized locations medial, lateral and anterior to the knee and the average joint-adjacent SCF (ajSCF) was calculated. Right thigh SCF cross-sectional area was assessed. Quantitative cartilage T2 relaxation times and semi-quantitative whole organ MRI scores (WORMS) were obtained at baseline and 4-year follow-up. WORMSsum was calculated as sum of cartilage, bone marrow edema, subchondral cyst, and meniscal scores. STATISTICAL TESTS: Associations of SCF measures with baseline, and 4-year change in T2 and WORMS were analyzed using regression models. SCF measurements were standardized using the equation ValueParticipant-MeanCohortStandard deviation . Analyses were adjusted for age, sex, physical activity, and BMI. RESULTS: Cross-sectionally, significant associations between lateral SCF, lateral compartment WORMS and T2 were found ( ΔWORMSsum1SDchange in lateralSCF , [95% CI]: 0.53, [0.12-0.95], P < 0.05; ΔT2 : 0.50, [0.02-0.98], P < 0.05). Moreover, greater lateral SCF was associated with faster progression of lateral WORMSsum gradings (OR = 1.50, [1.05-2.15], P < 0.05). No significant positive associations were found for thigh SCF and WORMSsum (P = 0.44) or T2 measurements (medial: P = 0.15, lateral: 0.39, patellar: P = 0.75). DATA CONCLUSION: Joint-adjacent SCF thickness was associated with imaging parameters of knee osteoarthritis, both cross-sectionally and longitudinally, while thigh SCF was not, suggesting a spatial association of SCF and knee osteoarthritis. Based on these findings, joint-adjacent SCF may play a role in the development and progression of knee osteoarthritis. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY: Stage 5.

Determining a Threshold of Medial Meniscal Extrusion for Prediction of Knee Pain and Cartilage Damage Progression Over 4 Years: Data From the Osteoarthritis Initiative.

BACKGROUND. The extent of medial meniscal extrusion (MME) that is associated with structural and symptomatic progression of knee osteoarthritis has not been defined yet. OBJECTIVE. The purpose of our study was to investigate MRI-based thresholds of MME that are associated with structural progression of knee degenerative disease and symptoms over a period of 4 years. METHODS. We studied 328 knees of 235 participants that were randomly selected from the Osteoarthritis Initiative cohort. MME was quantified on coronal sections of intermediate-weighted MRI sequences obtained at 3 T. Knee pain and cartilage abnormalities were measured using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scale and the cartilage whole-organ MRI score (WORMS). General estimating equations with logistic regression models were used to correlate baseline MME and changes in pain (WOMAC) and cartilage damage (WORMS). ROC analyses were performed to determine the area under the ROC curve (AUROC). Individual thresholds were determined by maximizing the product of sensitivity and specificity. RESULTS. The AUROC for predicting progression of knee pain, medial compartment cartilage damage, and medial tibial cartilage damage were 0.71, 0.70, and 0.72, respectively, and the individual thresholds for MME were 2.5, 2.7, and 2.8 mm. A single threshold of 2.5 mm was determined by maximizing the mean of the product of sensitivity and specificity of the three outcome variables (knee pain progression, medial compartmental cartilage damage progression, and medial tibial cartilage damage progression). CONCLUSION. MME was associated with knee pain and cartilage damage progression over 4 years. A single threshold of 2.5 mm was found to be the most useful threshold for predicting knee pain, medial compartment cartilage damage progression, and tibial cartilage damage progression over 4 years. CLINICAL IMPACT. This threshold could be used to standardize the diagnostic criterion of extrusion and to better characterize the risk for subsequent structural and symptomatic progression of knee osteoarthritis.

Lower urinary tract symptoms are associated with musculoskeletal pain among older men: Preliminary evidence for central sensitization as a mechanism?

AIMS: Features of central sensitization (CS) are present in almost all chronic pain conditions, including painful urinary conditions and back pain. Recently CS was proposed as a mechanism of nonpainful lower urinary tract symptoms (LUTS). Using musculoskeletal pain as an indicator of CS, we investigated whether the prevalence of musculoskeletal pain is greater among community-dwelling men with moderate or severe LUTS compared to those with mild LUTS. METHODS: We conducted a cross-sectional study of 5966 men ≥65 years who attended the Osteoporotic Fractures in Men Study baseline visit. LUTS were assessed with the American Urological Association Symptom Index (AUA-SI) and categorized as none/mild (0-7), moderate (8-19), or severe (≥20). Self-reported back, neck, hip, or knee pain within the 12 months before baseline was categorized as any pain and multilocation pain. We tested our hypothesis using odds ratios (OR) and 95% confidence intervals (CI) estimated from multivariable logistic regression models. RESULTS: The adjusted odds of any pain were higher among men with moderate (OR 1.49, 95% CI: 1.29-1.72) and severe LUTS (OR 1.76, 95% CI: 1.28-2.40) compared to those with no/mild LUTS. The adjusted odds of pain at ≥ 2 locations were 69% higher among men with moderate (OR 1.69, 95% CI: 1.45-196) and more than double among men with severe LUTS (OR 2.24, 95% CI: 1.62-3.10) compared to men with no/mild LUTS. CONCLUSIONS: Musculoskeletal pain, especially at multiple locations, is associated with greater LUTS severity among older men. CS may represent a novel shared mechanism of pain and LUTS.

Secondary analysis of change in physical function after exercise intervention in older adults with hyperkyphosis and low physical function.

BACKGROUND: Hyperkyphosis is common in older adults and associated with low physical function and reduced health related quality of life (HrQol). Improved kyphosis has been previously established in kyphosis-targeted interventions in randomized controlled trials in older adults with hyperkyphosis; however, evidence for improved physical function is conflicting. Few studies have investigated change in physical function after a targeted kyphosis intervention in older adults with low physical function. The primary aim in this descriptive study was to explore change in physical function after a progressive high-intensity 3-month targeted kyphosis exercise and posture training intervention in older adults with low physical function and hyperkyphosis. Secondary aims were to explore change in HrQol, spinal strength and spinal curvature, and adherence and safety of the intervention. METHODS: In this secondary analysis of the Specialized Center of Research (SCOR) Kyphosis randomized trial, 101 community dwelling older men and women with hyperkyphosis who completed the intervention were divided into a low function group (LFG) and high function group (HFG). Baseline characteristics were compared between LFG and HFG. Physical function, HrQol, spinal strength and spinal curvature (kyphosis and lordosis) pre/post intervention change scores were explored within and between groups. Adherence and adverse events were examined in the LFG and HFG. RESULTS: Twenty-six (26%) older adults were LFG, mean Short Phyiscal Performance Battery (SPPB) 9.62 (SD = 1.17) points. At baseline, the LFG was older than HFG (p = 0.005), experienced more pain, (p = 0.060), had worse physical function and HrQol (p ≤ 0.001), and comparable kyphosis (p = 0.640). SPPB changed 0.62 (95% CI: - 0.20 to 1.44) points in the LFG and - 0.04 (95%CI: - 0.28 to 0.19) points in the HFG, p = 0.020. Gait speed changed 0.04 (95% CI: - 0.02 to 0.10) m/s in the LFG. Kyphosis improved equally in both groups. Adherence to the intervention was 83% in the LFG and 79% in the HFG. There were no adverse events in either group. CONCLUSIONS: Older adults with low physical function and hyperkyphosis may improve physical function after a kyphosis targeted intervention. Older adults with low physical function may safely participate in targeted high-intensity kyphosis exercise and posture training. This observation needs to be confirmed in larger adequately powered studies. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01766674 .

Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain.

Back pain is the #1 cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this symptom. We conducted a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP). Adults of European ancestry were included from 15 cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and from the UK Biobank interim data release. CBP cases were defined as those reporting back pain present for ≥3-6 months; non-cases were included as comparisons ("controls"). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p<5×10(-8). Suggestive (p<5×10(-7)) and genome-wide significant (p<5×10(-8)) variants were carried forward for replication or further investigation in the remaining UK Biobank participants not included in the discovery sample. The discovery sample comprised 158,025 individuals, including 29,531 CBP cases. A genome-wide significant association was found for the intronic variant rs12310519 in SOX5 (OR 1.08, p = 7.2×10(-10)). This was subsequently replicated in 283,752 UK Biobank participants not included in the discovery sample, including 50,915 cases (OR 1.06, p = 5.3×10(-11)), and exceeded genome-wide significance in joint meta-analysis (OR 1.07, p = 4.5×10(-19)). We found suggestive associations at three other loci in the discovery sample, two of which exceeded genome-wide significance in joint meta-analysis: an intergenic variant, rs7833174, located between CCDC26 and GSDMC (OR 1.05, p = 4.4×10(-13)), and an intronic variant, rs4384683, in DCC (OR 0.97, p = 2.4×10(-10)). In this first reported meta-analysis of GWAS for CBP, we identified and replicated a genetic locus associated with CBP (SOX5). We also identified 2 other loci that reached genome-wide significance in a 2-stage joint meta-analysis (CCDC26/GSDMC and DCC).

Obese and overweight individuals have greater knee synovial inflammation and associated structural and cartilage compositional degeneration: data from the osteoarthritis initiative.

OBJECTIVE: This work aims to study (i) the relationship between body mass index (BMI) and knee synovial inflammation using non-contrast-enhanced MRI and (ii) the association of synovial inflammation versus degenerative abnormalities and pain. MATERIALS AND METHODS: Subjects with risk for and mild to moderate radiographic osteoarthritis were selected from the Osteoarthritis Initiative. Subjects were grouped into three BMI categories with 87 subjects per group: normal weight (BMI, 20-24.9 kg/m2), overweight (BMI, 25-29.9 kg/m2), and obese (BMI, ≥ 30 kg/m2), frequency matched for age, sex, race, Kellgren-Lawrence grade, and history of knee surgery and injury. Semi-quantitative synovial inflammation imaging biomarkers were obtained including effusion-synovitis, size and intensity of infrapatellar fat pad signal abnormality, and synovial proliferation score. Cartilage composition was measured using T2 relaxation time and structural abnormalities using the whole-organ magnetic resonance imaging score (WORMS). The Western Ontario and McMasters (WOMAC) Osteoarthritis Index was used for pain assessment. Intra- and inter-reader reproducibility was assessed by kappa values. RESULTS: Overweight and obese groups had higher prevalence and severity of all synovial inflammatory markers (p ≤ 0.03). Positive associations were found between synovial inflammation imaging biomarkers and average T2 values, WORMS maximum scores and total WOMAC pain scores (p < 0.05). Intra- and inter-reader kappa values for imaging biomarkers were high (0.76-1.00 and 0.60-0.94, respectively). CONCLUSION: Being overweight or obese was significantly associated with a greater prevalence and severity of synovial inflammation imaging biomarkers. Substantial reproducibility and high correlation with knee structural, cartilage compositional degeneration, and WOMAC pain scores validate the synovial inflammation biomarkers used in this study.