M K Javaid

Subchondral bone marrow lesions are highly associated with, and predict subchondral bone attrition longitudinally: the MOST study

OBJECTIVEnSubchondral bone attrition (SBA) is defined as flattening or depression of the osseous articular surface. The causes of attrition are unknown, but remodeling processes due to chronic overload that are reflected as bone marrow edema-like lesions (BMLs) on magnetic resonance imaging (MRI) might predispose the subchondral bone to subsequent attrition. The aim of this study was to evaluate the cross-sectional and longitudinal association of BMLs with SBA in the same subregion of the knee.nnnDESIGNnThe Multicenter Osteoarthritis (MOST) study is a longitudinal observational study of individuals who have or are at high risk for knee osteoarthritis. Subjects with available baseline and 30-months follow-up MRI were included. Patients with a recent history of trauma or findings suggestive of post-traumatic bone marrow changes were excluded. Subchondral BMLs and SBA were scored semiquantitatively from 0 to 3 in 10 tibiofemoral subregions. We evaluated the association of prevalent BMLs at baseline with the presence of prevalent and incident SBA on a per-subregion basis using logistic regression. We also cross-sectionally evaluated the association of BML grade severity and presence of baseline SBA.nnnRESULTSnOne thousand and twenty-five knees were included. 8.9% of the analyzed knee subregions showed SBA present at baseline and 9.2% of subregions exhibited prevalent subchondral BMLs. The adjusted odds ratio (OR) for prevalent SBA for subregions with prevalent BMLs was 18.8 [95% confidence intervals (CI) 15.9-22.4]. A larger BML size was directly associated with an increased risk of prevalent SBA. 195 (2.2%) subregions exhibited incident SBA at follow-up. The adjusted OR for incident SBA was 5.3 [95% CI 3.6-7.7] when compared to subregions without BMLs as the reference.nnnCONCLUSIONSnPrevalent and incident SBA is strongly associated with subchondral BMLs in the same subregion. One explanation for the presence and development of SBA is subchondral remodeling due to increased stress, which is reflected as BMLs on MRI.

High systemic bone mineral density increases the risk of incident knee OA and joint space narrowing, but not radiographic progression of existing knee OA: The MOST study

Objectives: Previous studies suggest that high systemic bone mineral density (BMD) is associated with incident knee osteoarthritis (OA) defined by osteophytes but not with joint space narrowing (JSN), and are inconsistent regarding BMD and progression of existing OA. The association of BMD with incident and progressive tibiofemoral OA was tested in a large prospective study of men and women aged 50–79 years with or at risk for knee OA. Methods: Baseline and 30-month weight-bearing posteroanterior and lateral knee radiographs were scored for Kellgren-Lawrence (K-L) grade, JSN and osteophytes. Incident OA was defined as the development of K-L grade ⩾2 at follow-up. All knees were classified for increases in grade of JSN and osteophytes from baseline. The association of gender-specific quartiles of baseline BMD with risk of incident and progressive OA was analysed using logistic regression, adjusting for covariates. Results: The mean (SD) age of 1754 subjects was 63.2 (7.8) years and body mass index was 29.9 (5.4) kg/m2. In knees without baseline OA, higher femoral neck and whole body BMD were associated with an increased risk of incident OA and increases in grade of JSN and osteophytes (p<0.01 for trends); adjusted odds were 2.3–2.9-fold greater in the highest compared with the lowest BMD quartiles. In knees with existing OA, progression was not significantly related to BMD. Conclusions: In knees without OA, higher systemic BMD was associated with a greater risk of the onset of JSN and K-L grade ⩾2. The role of systemic BMD in early knee OA pathogenesis warrants further investigation.

Pre-radiographic MRI findings are associated with onset of knee symptoms: the most study

OBJECTIVEnMagnetic resonance imaging (MRI) has greater sensitivity to detect osteoarthritis (OA) damage than radiographs but it is uncertain which MRI findings in early OA are clinically important. We examined MRI abnormalities detected in knees without radiographic OA and their association with incident knee symptoms.nnnMETHODnParticipants from the Multicenter Osteoarthritis Study (MOST) without frequent knee symptoms (FKS) at baseline were eligible if they also lacked radiographic features of OA at baseline. At 15 months, knees that developed FKS were defined as cases while control knees were drawn from those that remained without FKS. Baseline MRIs were scored at each subregion for cartilage lesions (CARTs); osteophytes (OST); bone marrow lesions (BML) and cysts. We compared cases and controls using marginal logistic regression models, adjusting for age, gender, race, body mass index (BMI), previous injury and clinic site.nnnRESULTSn36 case knees and 128 control knees were analyzed. MRI damage was common in both cases and controls. The presence of a severe CART (P=0.03), BML (P=0.02) or OST (P=0.02) in the whole knee joint was more common in cases while subchondral cysts did not differ significantly between cases and controls (P>0.1). Case status at 15 months was predicted by baseline damage at only two locations; a BML in the lateral patella (P=0.047) and at the tibial subspinous subregions (P=0.01).nnnCONCLUSIONnIn knees without significant symptoms or radiographic features of OA, MRI lesions of OA in only a few specific locations preceded onset of clinical symptoms and suggest that changes in bone play a role in the early development of knee pain. Confirmation of these findings in other prospective studies of knee OA is warranted.

Ankylosing Spondylitis Is Associated With an Increased Risk of Vertebral and Nonvertebral Clinical Fractures: A Population‐Based Cohort Study

The objective of this work was to study the associations between ankylosing spondylitis (AS) and clinical vertebral and nonvertebral fractures. Data from a large population‐based public health database in Spain, Sistema dInformació per al Desenvolupament de lInvestigació en Atenció Primària (SIDIAP), were used in this parallel cohort study. All participants registered in SIDIAP on January 1, 2006, were screened to identify those with a diagnosis of AS. Five age‐matched, gender‐matched, and general practice surgery–matched controls were selected for each patient with AS. All participants were followed until December 31, 2011, transfer out date, or death date. Fractures during this time were classified as vertebral or nonvertebral. Adjustment was made for potential confounders (tobacco smoking, alcohol consumption, body mass index, and use of oral steroids). Of 4,920,353 eligible patients in SIDIAP, 6474 AS patients with matched controls (nu2009=u200932,346) were available. A higher proportion of patients with AS versus controls had clinical vertebral (0.86% versus 0.41%) and nonvertebral (3.4% versus 2.7%) fractures. Adjusted Cox regression models showed an increased risk of clinical vertebral (hazard ratio [HR] 1.93; 95% confidence interval [CI], 1.39 to 2.68; pu2009<u20090.001) and nonvertebral (HR 1.19; 95% CI, 1.02 to 1.39; pu2009=u20090.03) fractures among patients with AS. However, the observed increased risks were apparent only in those not on regular nonsteroidal anti‐inflammatory drugs (NSAIDs). There were no interactions with inflammatory bowel disease, psoriasis, or previous back pain. Patients with AS are at increased risk of vertebral and nonvertebral clinical fractures, independently of various risk factors. Regular use of NSAIDs appears to eliminate the excess fracture risk related to AS, but the mechanisms involved are unknown.

Different indices of fetal growth predict bone size and volumetric density at 4 years of age

We have demonstrated previously that higher birth weight is associated with greater peak and later‐life bone mineral content and that maternal body build, diet, and lifestyle influence prenatal bone mineral accrual. To examine prenatal influences on bone health further, we related ultrasound measures of fetal growth to childhood bone size and density. We derived Z‐scores for fetal femur length and abdominal circumference and conditional growth velocity from 19 to 34 weeks gestation from ultrasound measurements in participants in the Southampton Womens Survey. A total of 380 of the offspring underwent dual‐energy X‐ray absorptiometry (DXA) at age 4 years [whole body minus head bone area (BA), bone mineral content (BMC), areal bone mineral density (aBMD), and estimated volumetric BMD (vBMD)]. Volumetric bone mineral density was estimated using BMC adjusted for BA, height, and weight. A higher velocity of 19‐ to 34‐week fetal femur growth was strongly associated with greater childhood skeletal size (BA: ru2009=u20090.30, pu2009<u2009.0001) but not with volumetric density (vBMD: ru2009=u20090.03, pu2009=u2009.51). Conversely, a higher velocity of 19‐ to 34‐week fetal abdominal growth was associated with greater childhood volumetric density (vBMD: ru2009=u20090.15, pu2009=u2009.004) but not with skeletal size (BA: ru2009=u20090.06, pu2009=u2009.21). Both fetal measurements were positively associated with BMC and aBMD, indices influenced by both size and density. The velocity of fetal femur length growth from 19 to 34 weeks gestation predicted childhood skeletal size at age 4 years, whereas the velocity of abdominal growth (a measure of liver volume and adiposity) predicted volumetric density. These results suggest a discordance between influences on skeletal size and volumetric density.

Changes in proximal femoral mineral geometry precede the onset of radiographic hip osteoarthritis: The study of osteoporotic fractures

OBJECTIVEnRadiographic hip osteoarthritis (RHOA) is associated with increased hip areal bone mineral density (aBMD). This study was undertaken to examine whether femoral geometry is associated with RHOA independent of aBMD.nnnMETHODSnParticipants in the Study of Osteoporotic Fractures in whom pelvic radiographs had been obtained at visits 1 and 5 (mean 8.3 years apart) and hip dual x-ray absorptiometry (DXA) had been performed (2 years after baseline) were included. Prevalent and incident RHOA phenotypes were defined as composite (osteophytes and joint space narrowing [JSN]), atrophic (JSN without osteophytes), or osteophytic (femoral osteophytes without JSN). Analogous definitions of progression were based on minimum joint space and total osteophyte score. Hip DXA scans were assessed using the Hip Structural Analysis program to derive geometric measures, including femoral neck length, width, and centroid position. Relative risks and 95% confidence intervals for prevalent, incident, and progressive RHOA per SD increase in geometric measure were estimated in a hip-based analysis using multinomial logistic regression with adjustment for age, body mass index, knee height, and total hip aBMD.nnnRESULTSnIn 5,245 women (mean age 72.6 years), a wider femoral neck with a more medial centroid position was associated with prevalent and incident osteophytic and composite RHOA phenotypes (P < 0.05). Increased neck width and centroid position were associated with osteophyte progression (both P < 0.05). No significant geometric associations with atrophic RHOA were found.nnnCONCLUSIONnDifferences in proximal femoral bone geometry and spatial distribution of bone mass occur early in hip OA and predict prevalent, incident, and progressive osteophytic and composite phenotypes, but not the atrophic phenotype. These bone differences may reflect responses to loading occurring early in the natural history of RHOA.

Maternal antenatal vitamin D status and offspring muscle development: findings from the Southampton Women's Survey

CONTEXTnMaternal 25-hydroxyvitamin D [25(OH)D] status in pregnancy has been associated with offspring bone development and adiposity. Vitamin D has also been implicated in postnatal muscle function, but little is known about a role for antenatal 25(OH)D exposure in programming muscle development.nnnOBJECTIVEnWe investigated the associations between maternal plasma 25(OH)D status at 34 weeks of gestation and offspring lean mass and muscle strength at 4 years of age.nnnDESIGN AND SETTINGnWe studied a prospective UK population-based mother-offspring cohort: the Southampton Womens Survey (SWS).nnnPARTICIPANTSnInitially, 12,583 nonpregnant women were recruited into the SWS, of whom 3159 had singleton pregnancies; 678 mother-child pairs were included in this analysis.nnnMAIN OUTCOMES MEASUREDnAt 4 years of age, offspring assessments included hand grip strength and whole-body dual-energy x-ray absorptiometry, yielding lean mass and percent lean mass. Physical activity was assessed by 7-day accelerometry in a subset of children (n=326).nnnRESULTSnThe maternal serum 25(OH)D concentration in pregnancy was positively associated with offspring height-adjusted hand grip strength (β=0.10 SD/SD, P=.013), which persisted after adjustment for maternal confounding factors, duration of breastfeeding, and childs physical activity at 4 years (β=0.13 SD/SD, P=.014). Maternal 25(OH)D was also positively associated with offspring percent lean mass (β=0.11 SD/SD, P=.006), but not total lean mass (β=0.06 SD/SD, P=.15). However, this association did not persist after adjustment for confounding factors (β=0.09 SD/SD, P=.11).nnnCONCLUSIONSnThis observational study suggests that intrauterine exposure to 25(OH)D during late pregnancy might influence offspring muscle development through an effect primarily on muscle strength rather than on muscle mass.

Dynamic Consent: a potential solution to some of the challenges of modern biomedical research.

BackgroundInnovations in technology have contributed to rapid changes in the way that modern biomedical research is carried out. Researchers are increasingly required to endorse adaptive and flexible approaches to accommodate these innovations and comply with ethical, legal and regulatory requirements. This paper explores how Dynamic Consent may provide solutions to address challenges encountered when researchers invite individuals to participate in research and follow them up over time in a continuously changing environment.MethodsAn interdisciplinary workshop jointly organised by the University of Oxford and the COST Action CHIP ME gathered clinicians, researchers, ethicists, lawyers, research participants and patient representatives to discuss experiences of using Dynamic Consent, and how such use may facilitate the conduct of specific research tasks. The data collected during the workshop were analysed using a content analysis approach.ResultsDynamic Consent can provide practical, sustainable and future-proof solutions to challenges related to participant recruitment, the attainment of informed consent, participant retention and consent management, and may bring economic efficiencies.ConclusionsDynamic Consent offers opportunities for ongoing communication between researchers and research participants that can positively impact research. Dynamic Consent supports inter-sector, cross-border approaches and large scale data-sharing. Whilst it is relatively easy to set up and maintain, its implementation will require that researchers re-consider their relationship with research participants and adopt new procedures.

Relationship between mortality and BMI after fracture: a population-based study of men and women aged ≥40 years.

Fractures in obese older individuals contribute significantly to the overall burden on primary health care, but data on their impact on mortality are lacking. We studied the association between obesity and mortality following hip and nonhip clinical fractures in a retrospective, population‐based cohort study. The Sistema dInformació pel Desenvolupament de la Investigació en Atenció Primària (SIDIAPQ) database contains primary care computerized medical records of a representative sample of >2.1 million people (35% of the population) in Catalonia (Spain), linked to hospital admissions data. We included in this analysis anyone aged 40 years and older suffering a hip or nonhip clinical fracture in 2007 to 2009 in the SIDIAPQ database. The main exposure was the most recent body mass index (BMI) measured before fracture, categorized as underweight (<18.5u2009kg/m2), normal (18.5 to <25u2009kg/m2), overweight (25 to <30u2009kg/m2), and obese (≥30u2009kg/m2). Furthermore, the study outcome was all‐cause mortality in 2007 to 2009 as provided to SIDIAPQ by the National Office of Statistics. Time to death after fracture was modeled using Cox regression. Multivariate models were adjusted for age, gender, smoking, alcohol intake, oral glucocorticoid use, and Charlson comorbidity index. Within the study period, 6988 and 29,372 subjects with a hip or nonhip clinical fracture were identified and followed for a median (interquartile range) of 1.17 (0.53–2.02) and 1.36 (0.65–2.15) years, respectively. Compared to subjects of normal weight, adjusted hazard ratios (HRs) for mortality in overweight and obese subjects were 0.74 (95% CI, 0.62–0.88; pu2009=u20090.001) and 0.74 (95% CI, 0.60–0.91; pu2009=u20090.004) after hip and 0.50 (95% CI, 0.32–0.77; pu2009=u20090.002), 0.56 (95% CI, 0.36–0.87; pu2009=u20090.010) after nonhip fracture. In conclusion, the highest mortality was observed in individuals with low BMI, but compared to subjects of normal weight, obese and overweight individuals survived longer following fracture. The latter observation is consistent with data reported in other chronic conditions, but the reasons for reduced mortality in obese and overweight subjects when compared to those of normal weight require further research.

Differences in glutamate receptors and inflammatory cell numbers are associated with the resolution of pain in human rotator cuff tendinopathy

IntroductionThe relationship between peripheral tissue characteristics and pain symptoms in soft tissue inflammation is poorly understood. The primary aim of this study was to determine immunohistochemical differences in tissue obtained from patients with persistent pain and patients who had become pain-free after surgical treatment for rotator cuff tendinopathy. The secondary aim was to investigate whether there would be differences in glutaminergic and inflammatory gene expression between disease-derived and healthy control cells in vitro.MethodsSupraspinatus tendon biopsies were obtained from nine patients with tendon pain before shoulder surgery and from nine further patients whose pain had resolved completely following shoulder surgery. Histological markers relating to the basic tendon characteristics, inflammation and glutaminergic signalling were quantified by immunohistochemical analysis. Gene expression of glutaminergic and inflammatory markers was determined in tenocyte explants derived from painful rotator cuff tendon tears in a separate cohort of patients and compared to that of explants from healthy control tendons. Dual labelling was performed to identify cell types expressing nociceptive neuromodulators.ResultsTendon samples from patients with persistent pain demonstrated increased levels of metabotropic glutamate receptor 2 (mGluR2), kainate receptor 1 (KA1), protein gene product 9.5 (PGP9.5), CD206 (macrophage marker) and CD45 (pan-leucocyte marker) versus pain-free controls (p <0.05). NMDAR1 co-localised with CD206-positive cells, whereas PGP9.5 and glutamate were predominantly expressed by resident tendon cells. These results were validated by in vitro increases in the expression of mGluR2, N-methyl-D-aspartate receptor (NMDAR1), KA1, CD45, CD206 and tumour necrosis factor alpha (TNF-α) genes (p <0.05) in disease-derived versus control cells.ConclusionsWe conclude that differences in glutamate receptors and inflammatory cell numbers are associated with the resolution of shoulder pain in rotator cuff tendinopathy, and that disease-derived cells exhibit a distinctly different neuro-inflammatory gene expression profile to healthy control cells.