Optimisation of vitamin D status in global populations.

Vitamin D is important for musculoskeletal health. Concentrations of 25-hydroxyvitamin D, the most commonly measured metabolite, vary markedly around the world and are influenced by many factors including sun exposure, skin pigmentation, covering, season and supplement use. Whilst overt vitamin D deficiency with biochemical consequences presents an increased risk of severe sequelae such as rickets, osteomalacia or cardiomyopathy and usually warrants prompt replacement treatment, the role of vitamin D supplementation in the population presents a different set of considerations. Here the issue is to keep, on average, the population at a level whereby the risk of adverse health outcomes in the population is minimised. This position paper, which complements recently published work from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases, addresses key considerations regarding vitamin D assessment and intervention from the population perspective. This position paper, on behalf of the International Osteoporosis Foundation Vitamin D Working Group, summarises the burden and possible amelioration of vitamin D deficiency in global populations. It addresses key issues including screening, supplementation and food fortification.

Do Soluble Phosphates Direct the Formose Reaction towards Pentose Sugars?

The formose reaction has been a leading hypothesis for the prebiotic synthesis of sugars such as ribose for many decades but tends to produce complex mixtures of sugars and often tars. Channeling the formose reaction towards the synthesis of biologically useful sugars such as ribose has been a holy grail of origins-of-life research. Here, we tested the hypothesis that a simple, prebiotically plausible phosphorylating agent, acetyl phosphate, could direct the formose reaction towards ribose through phosphorylation of intermediates in a manner resembling gluconeogenesis and the pentose phosphate pathway. We did indeed find that addition of acetyl phosphate to a developing formose reaction stabilized pentoses, including ribose, such that after 5 h of reaction about 10-fold more ribose remained compared with control runs. But mechanistic analyses using liquid chromatography-mass spectrometry showed that, far from being directed towards ribose by phosphorylation, the formose reaction was halted by the precipitation of Ca2+ ions as phosphate minerals such as apatite and hydroxyapatite. Adding orthophosphate had the same effect. Phosphorylated sugars were only detected below the limit of quantification when adding acetyl phosphate. Nonetheless, our findings are not strictly negative. The sensitivity of the formose reaction to geochemically reasonable conditions, combined with the apparent stability of ribose under these conditions, serves as a valuable constraint on possible pathways of sugar synthesis at the origin of life.

Effusion-synovitis worsening mediates the association between body mass index and Kellgren-Lawrence progression in obese individuals: data from the Osteoarthritis Initiative.

OBJECTIVE: Both obesity and synovitis are independently associated with knee osteoarthritis (KOA) progression. We examined whether synovitis mediates the relationship between body mass index (BMI) and KOA radiographic progression in the Osteoarthritis Initiative (OAI) cohort. DESIGN: We conducted a case-control study within the OAI. Cases (n = 315) were right knees with an increase of ≥1 Kellgren-Lawrence from baseline to 48 months of follow-up. Controls (n = 315) were right knees with no KL change. Cases and controls were matched by age, sex, race, and baseline KL. MRI Osteoarthritis Knee Score (MOAKS) at baseline and at 2 years was used for a semi-quantitative scoring (0-3) of effusion-synovitis and Hoffa-synovitis. Conditional logistic regression estimated associations between BMI and synovitis with KOA progression. Mediation analysis was used to assess the mediating effects of synovitis. RESULTS: The mean age of participants was 61 years, 70.8% were women, and 87% were White. KOA progression was associated with higher BMI (adjusted OR 1.05; 95%CI 1.01-1.09) and effusion-synovitis relative to no effusion-synovitis (adjusted OR 2.2; 95%CI 1.6-3.1). Associations between effusion-synovitis worsening and KOA progression were more pronounced among obese individuals (OR 34.1; 95%CI 4.2-274.8; P = 0.001) compared to normal weight (OR 3.2; 95%CI 0.8-12.8, P=0.096) individuals. Effusion-synovitis at 2 years, but not at baseline, mediated the relationship between BMI and KOA progression over a 4-year period. CONCLUSIONS: We found that effusion-synovitis worsening mediated the association between BMI and KOA progression and was associated with increased risk of KOA progression, particularly among obese individuals.

Measuring school level attributable risk to support school-based HPV vaccination programs.

BACKGROUND: In Australia in 2017, 89% of 15-year-old females and 86% of 15-year-old males had received at least one dose of the HPV vaccine. However, considerable variation in HPV vaccination initiation (dose one) across schools remains. It is important to understand the school-level characteristics most strongly associated with low initiation and their contribution to the overall between-school variation. METHODS: A population-based ecological analysis was conducted using school-level data for 2016 on all adolescent students eligible for HPV vaccination in three Australian jurisdictions. We conducted logistic regression to determine school-level factors associated with lower HPV vaccination initiation (< 75% dose 1 uptake) and estimated the population attributable risk (PAR) and the proportion of schools with the factor (school-level prevalence). RESULTS: The factors most strongly associated with lower initiation, and their prevalence were; small schools (OR = 9.3, 95%CI = 6.1-14.1; 33% of schools), special education schools (OR = 5.6,95%CI = 3.7-8.5; 8% of schools), higher Indigenous enrolments (OR = 2.7,95% CI:1.9-3.7; 31% of schools), lower attendance rates (OR = 2.6,95%CI = 1.7-3.7; 35% of schools), remote location (OR = 2.6,95%CI = 1.6-4.3; 6% of schools,) and lower socioeconomic area (OR = 1.8,95% CI = 1.3-2.5; 33% of schools). The highest PARs were small schools (PAR = 79%, 95%CI:76-82), higher Indigenous enrolments (PAR = 38%, 95%CI: 31-44) and lower attendance rate (PAR = 37%, 95%CI: 29-46). CONCLUSION: This analysis suggests that initiatives to support schools that are smaller, with a higher proportion of Indigenous adolescents and lower attendance rates may contribute most to reducing the variation of HPV vaccination uptake observed at a school-level in these jurisdictions. Estimating population-level coverage at the school-level is useful to guide policy and prioritise resourcing to support school-based vaccination programs.

The global approach to rehabilitation following an osteoporotic fragility fracture: A review of the rehabilitation working group of the International Osteoporosis Foundation (IOF) committee of scientific advisors.

PURPOSE: To conduct a review of the current state of the evidence for rehabilitation strategies post-fragility fracture. METHODS: Narrative review conducted by the Rehabilitation Working Group of the International Osteoporosis Foundation Committee of Scientific Advisors characterizing the range of rehabilitation modalities instrumental for the management of fragility fractures. RESULTS: Multi-modal exercise post-fragility fracture to the spine and hip is strongly recommended to reduce pain, improve physical function, and improve quality of life. Outpatient physiotherapy post-hip fracture has a stronger evidence base than outpatient physiotherapy post-vertebral fracture. Appropriate nutritional care after fragility fracture provides a large range of improvement in morbidity and mortality. Education increases understanding of osteoporosis which in turn increases utilization of other rehabilitation services. Education may improve other health outcomes such as pain and increase a patient's ability for self-advocacy. CONCLUSION: Rehabilitation interventions are inter-reliant, and research investigating the interaction of exercise, nutrition, and other multi-modal therapies may increase the relevance of rehabilitation research to clinical care.

Differences in school factors associated with adolescent HPV vaccination initiation and completion coverage in three Australian states.

BACKGROUND: Schools are the primary setting for the delivery of adolescent HPV vaccination in Australia. Although this strategy has achieved generally high vaccination coverage, gaps persist for reasons that are mostly unknown. This study sought to identify school-level correlates of low vaccination course initiation and completion in New South Wales, Tasmania, and Western Australia to inform initiatives to increase uptake. METHODS: Initiation was defined as the number of first doses given in a school in 2016 divided by vaccine-eligible student enrolments. Completion was the number of third doses given in a school in 2015-2016 divided by the number of first doses. Low initiation and completion were defined as coverage ≤ 25thpercentile of all reporting schools. We investigated correlations between covariates using Spearman's rank correlation coefficients. Due to multicollinearity, we used univariable logistic regression to investigate associations between school characteristics and low coverage. RESULTS: Median initiation was 84.7% (IQR: 75.0%-90.4%) across 1,286 schools and median completion was 93.8% (IQR: 86.0%-97.3%) across 1,295 schools. There were strong correlations between a number of school characteristics, particularly higher Indigenous student enrolments and lower attendance, increasing remoteness, higher postcode socioeconomic disadvantage, and smaller school size. Characteristics most strongly associated with low initiation in univariate analyses were small school size, location in Tasmania, and schools catering for special educational needs. Low completion was most strongly associated with schools in Tasmania and Western Australia, remote location, small size, high proportion of Indigenous student enrolments, and low attendance rates. CONCLUSION: This study provides indicative evidence that characteristics of schools and school populations are associated with the likelihood of low initiation and completion of the HPV vaccination course. The findings will guide further research and help target initiatives to improve vaccination uptake in schools with profiles associated with lower coverage.

Association between bariatric surgery with long-term analgesic prescription and all-cause mortality among patients with osteoarthritis: a general population-based cohort study.

OBJECTIVES: There is still a large unmet need for novel osteoarthritis (OA) treatments that could provide clinically important effects on long-term pain relief (≥12 months). We examined the relation of bariatric surgery along with weight loss to analgesic prescription and all-cause mortality among individuals with OA. METHODS: We conducted a cohort study among individuals with OA using The Health Improvement Network. We compared the rate of no analgesic prescription ≥12 consecutive months and the risk of all-cause mortality using inverse probability weighting Cox-proportional hazard models and the difference in number of analgesic prescriptions (non-steroidal anti-inflammatory drugs, opioids, and paracetamol) in the 50th, 75th and 90th percentiles using quantile regression model between bariatric and non-bariatric cohorts. RESULTS: Included were 588,494 individuals (694 had bariatric surgery). Compared with non-bariatric group, the rate of no analgesic prescription ≥12 consecutive months was higher (HR = 1.23, 95% CI: 1.08-1.38) in bariatric surgery group, and the number of analgesic prescriptions was lower in the 75th (44 vs 58) and 90th (74 vs 106) percentiles during a mean follow-up of 4.3 years. All-cause mortality in bariatric surgery group was lower than comparison group (HR = 0.46, 95% CI: 0.41-0.51). CONCLUSION: This study presents the first evidence that bariatric surgery was associated with decreased long-term analgesic prescription and decreased all-cause mortality among individuals with OA. However, our findings may be overestimated owing to intractable confounding by indication for bariatric surgery; thus, future studies (e.g., clinical trials) are warranted.

Effect of portable noninvasive ventilation on thoracoabdominal volumes in recovery from intermittent exercise in patients with COPD.

We previously showed that use of portable noninvasive ventilation (pNIV) during recovery periods within intermittent exercise improved breathlessness and exercise tolerance in patients with COPD compared with pursed-lip breathing (PLB). However, in a minority of patients recovery from dynamic hyperinflation (DH) was better with PLB, based on inspiratory capacity. We further explored this using Optoelectronic Plethysmography to assess total and compartmental thoracoabdominal volumes. Fourteen patients with COPD (means ± SD) (FEV1: 55% ± 22% predicted) underwent, in a balanced order sequence, two intermittent exercise protocols on the cycle ergometer consisting of five repeated 2-min exercise bouts at 80% peak capacity, separated by 2-min recovery periods, with application of pNIV or PLB in the 5 min of recovery. Our findings identified seven patients showing recovery in DH with pNIV (DH responders) whereas seven showed similar or better recovery in DH with PLB. When pNIV was applied, DH responders compared with DH nonresponders exhibited greater tidal volume (by 0.8 ± 0.3 L, P = 0.015), inspiratory flow rate (by 0.6 ± 0.5 L/s, P = 0.049), prolonged expiratory time (by 0.6 ± 0.5 s, P = 0.006), and duty cycle (by 0.7 ± 0.6 s, P = 0.007). DH responders showed a reduction in end-expiratory thoracoabdominal DH (by 265 ± 633 mL) predominantly driven by reduction in the abdominal compartment (by 210 ± 494 mL); this effectively offset end-inspiratory rib-cage DH. Compared with DH nonresponders, DH responders had significantly greater body mass index (BMI) by 8.4 ± 3.2 kg/m2, P = 0.022 and tended toward less severe resting hyperinflation by 0.3 ± 0.3 L. Patients with COPD who mitigate end-expiratory rib-cage DH by expiratory abdominal muscle recruitment benefit from pNIV application.NEW & NOTEWORTHY Compared with the pursed-lip breathing technique, acute application of portable noninvasive ventilation during recovery from intermittent exercise improved end-expiratory thoracoabdominal dynamic hyperinflation (DH) in 50% of patients with COPD (DH responders). DH responders, compared with DH nonresponders, exhibited a reduction in end-expiratory thoracoabdominal DH predominantly driven by the abdominal compartment that effectively offset end-expiratory rib cage DH. The essential difference between DH responders and DH nonresponders was, therefore, in the behavior of the abdomen.

A Phase 2b randomized trial of lorecivivint, a novel intra-articular CLK2/DYRK1A inhibitor and Wnt pathway modulator for knee osteoarthritis.

OBJECTIVE: Lorecivivint (LOR; SM04690), an investigational Wnt pathway modulator, previously demonstrated patient-reported and radiographic outcome improvements vs placebo in clinically relevant subjects with moderate to severe knee osteoarthritis (OA). This study's objective was to identify effective LOR doses. DESIGN: Subjects in this 24-week, Phase 2b, multicenter, randomized, double-blind, placebo (PBO)-controlled trial received an intra-articular injection of 2 mL LOR (0.03, 0.07, 0.15, or 0.23 mg), PBO, or dry-needle sham. The primary efficacy endpoints were changes in Pain NRS [0-10], WOMAC Pain [0-100], WOMAC Function [0-100], and radiographic mJSW outcomes, which were measured using baseline-adjusted analysis of covariance at Week 24. Multiple Comparison Procedure-Modeling (MCP-Mod) was performed for dose modeling. RESULTS: In total, 695/700 subjects were treated. Pain NRS showed significant improvements vs PBO after treatment with 0.07 mg and 0.23 mg LOR at Weeks 12 (-0.96, 95% CI [-1.54, -0.37], P = 0.001; -0.78 [-1.39, -0.17], P = 0.012) and 24 (-0.70 [-1.34, -0.06], P = 0.031; -0.82 [-1.51, -0.12], P = 0.022). Additionally, 0.07 mg LOR significantly improved WOMAC Pain and Function subscores vs PBO at Week 12 (P = 0.04, P = 0.021), and 0.23 mg LOR significantly improved both WOMAC subscores at Week 24 (P = 0.031, P = 0.017). No significant differences from PBO were observed for other doses. No radiographic progression was observed in any group at Week 24. MCP-Mod identified 0.07 mg LOR as the lowest effective dose. CONCLUSION: This 24-week Phase 2b trial demonstrated the efficacy of LOR on PROs in knee OA subjects. The optimal dose for future studies was identified as 0.07 mg LOR.

Statistical shape modeling of the hip and the association with hip osteoarthritis: a systematic review.

OBJECTIVE: To summarize available evidence on the association between hip shape as quantified by statistical shape modeling (SSM) and the incidence or progression of hip osteoarthritis. DESIGN: We conducted a systematic search of five electronic databases, based on a registered protocol (available: PROSPERO CRD42020145411). Articles presenting original data on the longitudinal relationship between radiographic hip shape (quantified by SSM) and hip OA were eligible. Quantitative meta-analysis was precluded because of the use of different SSM models across studies. We used the Newcastle-Ottawa Scale (NOS) for risk of bias assessment. RESULTS: Nine studies (6,483 hips analyzed with SSM) were included in this review. The SSM models used to describe hip shape ranged from 16 points on the femoral head to 85 points on the proximal femur and hemipelvis. Multiple hip shape features and combinations thereof were associated with incident or progressive hip OA. Shape variants that seemed to be consistently associated with hip OA across studies were acetabular dysplasia, cam morphology, and deviations in acetabular version (either excessive anteversion or retroversion). CONCLUSIONS: Various radiographic, SSM-defined hip shape features are associated with hip OA. Some hip shape features only seem to increase the risk for hip OA when combined together. The heterogeneity of the used SSM models across studies precludes the estimation of pooled effect sizes. Further studies using the same SSM model and definition of hip OA are needed to allow for the comparison of outcomes across studies, and to validate the found associations.

Sleep duration and bone health measures in older men.

The associations between objective measures of sleep duration and bone outcomes in older men are unknown. No consistent, significant association was identified between sleep duration and bone mineral density (BMD) in the current analysis. However, future research should determine if vitamin D status modifies this relationship. INTRODUCTION: Prior studies, predominantly in women, reported that long and short self-reported sleep duration are associated with lower BMD. Associations between actigraphy-determined sleep duration and BMD or bone turnover markers (BTMs) in older men are unknown. METHODS: Men in The Osteoporotic Fractures in Men (MrOS) Study with wrist actigraphy and concurrent BMD assessment but without comorbidities affecting bone health were included. Sleep duration was considered as a continuous (N = 1926) and dichotomized variable where men were classified as getting the recommended (7-8 h/night; N = 478) or short (< 6 h/night; N = 577) sleep. The cross-sectional association between BMD, BTMs, and sleep duration was examined using a t test or linear regression, where appropriate, in unadjusted and adjusted models. RESULTS: There were no clinically or statistically significant differences in BMD at the L-spine, total hip, or femoral neck between men getting the recommended vs. short sleep duration, using actigraphy or self-reported sleep duration (all p ≥ 0.07). When sleep duration was considered as a continuous variable, femoral neck BMD was higher in men with longer self-reported sleep duration (ß = 0.006 ±0.003, p = 0.02), but this was not significant after further adjustment. In men with low 25OHD (< 20 ng/mL), longer actigraphy-determined sleep duration was associated with higher total hip BMD (ß = 0.016 ± 0.008; p = 0.04). Sleep duration and BTMs were not associated. CONCLUSION: Sleep duration was not associated with hip or L-spine BMD or BTMs in older men. Future research should determine if vitamin D status or other factors modify this relationship.

Real-world bone turnover marker use: impact on treatment decisions and fracture.

The use of bone turnover marker (BTM) testing for patients with osteoporosis in the USA has not been well characterized. This retrospective US-based real-world data study found BTM testing has some association with treatment decision-making and lower fracture risk in patients with presumed osteoporosis, supporting its use in clinical practice. INTRODUCTION: The purpose of this study was to characterize bone turnover marker (BTM) testing patterns and estimate their clinical utility in treatment decision-making and fragility fracture risk in patients with osteoporosis using a retrospective claims database. METHODS: Data from patients aged ≥ 50 years with newly diagnosed osteoporosis enrolled in the Truven MarketScan® Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases from January 2008 to June 2018 were included. Osteoporosis was ascertained by explicit claims, fragility fracture events associated with osteoporosis, or prescribed anti-resorptive or anabolic therapy. BTM-tested patients were 1:1 propensity score matched to those untested following diagnosis. Generalized estimating equation models were performed to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for testing versus no testing on both treatment decision-making and fragility fracture. RESULTS: Of the 457,829 patients with osteoporosis, 6075 were identified with ≥ 1 BTM test following diagnosis; of these patients, 1345 had a unique treatment decision made ≤ 30 days from BTM testing. The percentage of patients receiving BTM tests increased significantly each year (average annual % change: + 8.1%; 95% CI: 5.6-9.0; p = 0.01). Patients tested were significantly more likely to have a treatment decision (OR: 1.14; 95% CI: 1.13-1.15), and testing was associated with lower odds of fracture versus those untested (OR: 0.87; 95% CI: 0.85-0.88). CONCLUSION: In this large, heterogeneous population of patients with presumed osteoporosis, BTM testing was associated with treatment decision-making, likely leading to fragility fracture reduction following use.

Low Protein Intake Irrespective of Source is Associated with Higher Mortality Among Older Community-dwelling Men.

OBJECTIVES: Our aim was to determine the association between protein intake (overall and by source) and all-cause and cause-specific mortality among older men. DESIGN: Prospective cohort study. SETTING: 5790 ambulatory community-dwelling older men from multicenter Osteoporotic Fractures in Men (MrOS) study. MEASUREMENTS: Total energy and protein intake, and protein intake by source (dairy, non-dairy animal, plant) were assessed using a 69-item food frequency questionnaire. We included up to 10-year follow-up with adjudicated cardiovascular, cancer and other mortality outcomes. We used time-to-event analysis with protein exposures, mortality outcome, and adjusted for possible confounders including age, center, education, race, smoking, alcohol use, physical activity, weight, total energy intake (TEI), and comorbidities. Hazard ratios were expressed per each unit=2.9% TEI decrement for all protein intake variables. RESULTS: The mean (SD) baseline age of 5790 men was 73.6 (5.8) y. There were 1611 deaths and 211 drop-outs prior to 10 years, and 3868 men who were alive at the 10-year follow-up. The mean (SD) total protein intake was 64.7 (25.8) g/d, while the mean (SD) intake expressed as percent of total energy intake (%TEI) was 16.1 (2.9) %TEI. Lower protein intake was associated with an increased risk of death, with unadjusted HR=1.11 (95% CI: 1.06, 1.17) and adjusted HR=1.09 (95% CI: 1.04, 1.14) and the associations for protein intake by source were similar. The adjusted HR for cancer mortality was HR=1.13 (95% CI: 1.03, 1.25) while the association for CVD mortality was HR=1.08 (95% CI: 0.99, 1.18). CONCLUSIONS: Low protein intake, irrespective of source, was associated with a modest increase in risk of all-cause and cause-specific mortality among older men. Special consideration should be given to level of protein intake among older adults.

Climate drives the geography of marine consumption by changing predator communities.

The global distribution of primary production and consumption by humans (fisheries) is well-documented, but we have no map linking the central ecological process of consumption within food webs to temperature and other ecological drivers. Using standardized assays that span 105° of latitude on four continents, we show that rates of bait consumption by generalist predators in shallow marine ecosystems are tightly linked to both temperature and the composition of consumer assemblages. Unexpectedly, rates of consumption peaked at midlatitudes (25 to 35°) in both Northern and Southern Hemispheres across both seagrass and unvegetated sediment habitats. This pattern contrasts with terrestrial systems, where biotic interactions reportedly weaken away from the equator, but it parallels an emerging pattern of a subtropical peak in marine biodiversity. The higher consumption at midlatitudes was closely related to the type of consumers present, which explained rates of consumption better than consumer density, biomass, species diversity, or habitat. Indeed, the apparent effect of temperature on consumption was mostly driven by temperature-associated turnover in consumer community composition. Our findings reinforce the key influence of climate warming on altered species composition and highlight its implications for the functioning of Earth's ecosystems.

Subregional statistical shape modelling identifies lesser trochanter size as a possible risk factor for radiographic hip osteoarthritis, a cross-sectional analysis from the Osteoporotic Fractures in Men Study.

OBJECTIVE: Statistical shape modelling (SSM) of hip dual-energy X-ray absorptiometry (DXA) scans has identified relationships between hip shape and radiographic hip OA (rHOA). We aimed to further elucidate shape characteristics related to rHOA by focusing on subregions identified from whole-hip shape models. METHOD: SSM was applied to hip DXAs obtained in the Osteoporotic Fractures in Men Study. Whole-hip shape modes (HSMs) associated with rHOA were combined to form a composite at-risk-shape. Subsequently, subregional HSMs (cam-type and lesser trochanter modes) were built, and associations with rHOA were examined by logistic regression. Subregional HSMs were further characterised, by examining associations with 3D-HSMs derived from concurrent hip CT scans. RESULTS: 4,098 participants were identified with hip DXAs and radiographs. Composite shapes from whole-hip HSMs revealed that lesser trochanter size and cam-type femoral head are related to rHOA. From sub-regional models, lesser trochanter mode (LTM)1 [OR 0.74; 95%CI 0.63.0.87] and cam-type mode (CTM)3 [OR 1.27; 1.13.1.42] were associated with rHOA, associations being similar to those for whole hip HSMs. 515 MrOS participants had hip DXAs and 3D-HSMs derived from hip CT scans. LTM1 was associated with 3D-HSMs that also represented a larger lesser trochanter [3D-HSM7 (beta (ß)-0.23;-0.33,-0.14) and 3D-HSM9 (ß0.36; 0.27.0.45)], and CTM3 with 3D-HSMs describing cam morphology [3D-HSM3 (ß-0.16;-0.25,-0.07) and 3D-HSM6 (ß 0.19; 0.10.0.28)]. CONCLUSION: Subregional SSM of hip DXA scans suggested larger lesser trochanter and cam morphology underlie associations between overall hip shape and rHOA. 3D hip modelling suggests our subregional SSMs represent true anatomical variations in hip shape, warranting further investigation.

Chondrocalcinosis is associated with increased knee joint degeneration over 4 years: data from the Osteoarthritis Initiative.

OBJECTIVE: To determine if presence of calcium-containing crystals (CaC) is associated with increased knee joint degeneration over 4 years and assess if total number of CaCs deposited is a useful measure of disease burden. DESIGN: Seventy subjects with CaCs in right knees at baseline were selected from the Osteoarthritis Initiative and matched to 70 subjects without evidence of CaCs. T1-weighted gradient-echo sequences were used to confirm presence of CaCs and count the numbers of distinct circumscribed CaCs. Morphological abnormalities were assessed at baseline and 4-year follow-up using the modified semi-quantitative Whole-Organ Magnetic Resonance Imaging Score (WORMS). Linear regression models were used to analyze the associations between presence of CaCs at baseline and changes in WORMS and to analyze the associations between numbers of circumscribed CaCs at baseline and changes in WORMS. RESULTS: Presence of CaCs was associated with increased cartilage degeneration in the patella (coefficient: 0.33; 95% confidence interval (CI): 0.04-0.63), the medial femur (coefficient: 0.51; 95% CI: 0.18-0.83), the lateral tibia (coefficient: 0.36; 95% CI: 0.01-0.71) as well as the medial and lateral meniscus (coefficient: 0.38; 95% CI: 0.00-0.75 and coefficient: 0.72; 95% CI: 0.12-1.32). Knees with higher numbers of CaCs had increased cartilage degeneration in the patella and medial femur (coefficient: 0.09; 95% CI: 0.05-0.14; P < 0.001 and coefficient: 0.08; 95% CI: 0.02-0.14; P = 0.005). CONCLUSIONS: CaCs were associated with increased cartilage and meniscus degeneration over a period of 4 years. Assessing the number of CaC depositions may be useful to evaluate risk of onset and worsening of degenerative disease.

Tropomyosin-related kinase A (TrkA) inhibition for the treatment of painful knee osteoarthritis: results from a randomized controlled phase 2a trial.

OBJECTIVE: To investigate the TrkA inhibitor, ASP7962, for treatment of painful knee osteoarthritis. DESIGN: Phase 2a, double-blind, placebo- and naproxen-controlled, double-dummy, parallel-group study. Adults with knee osteoarthritis were randomized (2:2:1) to ASP7962 (100 mg), placebo, or naproxen (500 mg) twice daily (BID) for 4 weeks. Primary endpoint: change from baseline to Week 4 in Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain subscale score. Secondary endpoints: change from baseline to Weeks 1, 2, and End of Treatment (EoT) in WOMAC pain subscale score; change from baseline to Weeks 1, 2, 4, and EoT in WOMAC physical function and stiffness subscales, walking pain and WOMAC total scores; and change from baseline in daily average pain score. RESULTS: 215 participants were randomized (ASP7962 100 mg BID, n = 85; placebo, n = 87; naproxen 500 mg BID, n = 43). No significant difference was observed between ASP7962 and placebo in change from baseline to Week 4 in WOMAC pain subscale score (-0.14; 90% 2-sided CI: -0.62, 0.34; P = 0.316); a significant difference was observed between naproxen and placebo (-0.67; 80% 2-sided CI: -1.12, -0.23; P = 0.027). No differences were observed between ASP7962 and placebo in change from baseline in any WOMAC subscale score; statistically significant changes were observed between naproxen and placebo (P ≤ 0.01, all time points for all WOMAC endpoints). ASP7962 was safe and well-tolerated. CONCLUSIONS: Four-week treatment with ASP7962 (100 mg BID) did not improve pain or physical function in individuals with painful knee osteoarthritis. ClinicalTrials.gov, NCT02611466; EudraCT Number, 2014-004996-22.

Inhibition of vascular endothelial growth factor in young adult mice causes low bone blood flow and bone strength with no effect on bone mass in trabecular regions.

OBJECTIVE: To determine the effect of an antibody to vascular endothelial growth factor (VEGF) on bone blood flow, bone strength, and bone mass in the young adult mouse. METHODS: Ten-week-old male BALB/cJ mice were body weight-randomized into either a rodent anti-VEGF monoclonal antibody (anti-VEGF, B20-4.1.1; 5 mg/kg 2×/wk.; n = 12) group or a vehicle (VEH; n = 12) group. After 42 days, mice were evaluated for bone blood flow at the distal femur by 18F-NaF-PET/CT and then necropsied. Samples from trabecular and cortical bone regions were evaluated for bone strength by mechanical testing, bone mass by peripheral quantitative computed tomography (pQCT), and micoarchitecture (MicroCT). Hydration of the whole femur was studied by proton nuclear magnetic resonance relaxometry (1H NMR). RESULTS: Distal femur blood flow was 43% lower in anti-VEGF mice than in VEH mice (p = 0.009). Ultimate load in the lumbar vertebral body was 25% lower in anti-VEGF than in VEH mice (p = 0.013). Bone mineral density (BMD) in the trabecular region of the proximal humeral metaphysis by pQCT, and bone volume fraction and volumetric BMD by MicroCT were the same in the two groups. Volume fraction of bound water (BW) of the whole femur was 14% lower in anti-VEGF than in VEH mice (p = 0.003). Finally, BW, but not cortical tissue mineral density, helped section modulus explain the variance in the ultimate moment experienced by the femur in three-point bending. CONCLUSION: Anti-VEGF caused low bone blood flow and bone strength in trabecular bone regions without influencing BMD and microarchitecture. Low bone strength was also associated with low bone hydration. These data suggest that bone blood flow is a novel bone property that affects bone quality.

Intra-articular corticosteroids and the risk of knee osteoarthritis progression: results from the Osteoarthritis Initiative.

OBJECTIVE: A recent randomized clinical trial reported that repeated intra-articular corticosteroids (IACs) were associated with a greater cartilage loss. This study aimed to examine the relation of IACs to knee radiographic osteoarthritis (ROA) progression in a real-world setting. DESIGN: A cohort that initiated IACs and a comparison cohort without IACs from participants with mild to moderate knee ROA in the Osteoarthritis Initiative (OAI) were assembled (from 0-month to 48-month). Two measures of knee ROA progression were assessed during the follow-up period: (1) an increase in Kellgren and Lawrence (KL) grade by ≥1 grade or having a knee replacement (i.e., KL grade worsening); and (2) a decrease in joint space width (JSW) by ≥0.7 mm or having a knee replacement (i.e., JSW worsening). The associations of IACs initiation using a propensity-score matched cohort study and continuous IACs using marginal structural models with the risk of knee ROA progression were examined. RESULTS: Among 684 propensity-score matched participants at baseline (148 IACs initiators, 536 comparators), 65 knees (21.7/100 person-years) in the IACs initiation cohort and 90 knees (7.1/100 person-years) in the comparison cohort experienced KL worsening. The hazard ratios (HRs) of KL worsening from IACs initiation and continuous IACs were 3.02 (95% confidence interval [CI], 2.19-4.16) and 4.67 (95% CI, 2.92-7.47), respectively. The corresponding HRs of JSW worsening were 2.93 (95% CI, 2.13-4.02) and 3.26 (95% CI, 1.78-5.96), respectively. All HRs for continuous use of IACs were further away from the null. CONCLUSIONS: IACs, especially continuous IACs, may be associated with an increased risk of knee ROA progression.