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Objectives To examine whether acetabular dysplasia (AD), cam and/or pincer morphology are associated with radiographic hip osteoarthritis (rHOA) and hip pain in UK Biobank (UKB) and, if so, what distribution of osteophytes is observed.DesignParticipants from UKB with a left hip dual-energy x-ray absorptiometry (DXA) scan had alpha angle (AA), lateral centre-edge angle (LCEA) and joint space narrowing (JSN) derived automatically. Cam and pincer morphology, and AD were defined using AA and LCEA. Osteophytes were measured manually and rHOA grades were calculated from JSN and osteophyte measures. Logistic regression was used to examine the relationships between these hip morphologies and rHOA, osteophytes, JSN, and hip pain.Results6,807 individuals were selected (mean age: 62.7; 3382/3425 males/females). Cam morphology was more prevalent in males than females (15.4% and 1.8% respectively). In males, cam morphology was associated with rHOA [OR 3.20 (95% CI 2.41-4.25)], JSN [1.53 (1.24-1.88)], and acetabular [1.87 (1.48-2.36)], superior [1.94 (1.45-2.57)] and inferior [4.75 (3.44-6.57)] femoral osteophytes, and hip pain [1.48 (1.05-2.09)]. Broadly similar associations were seen in females, but with weaker statistical evidence. Neither pincer morphology nor AD showed any associations with rHOA or hip pain.ConclusionsCam morphology was predominantly seen in males in whom it was associated with rHOA and hip pain. In males and females, cam morphology was associated with inferior femoral head osteophytes more strongly than those at the superior femoral head and acetabulum. Further studies are justified to characterise the biomechanical disturbances associated with cam morphology, underlying the observed osteophyte distribution.

Spine shape changes dramatically in early life, influenced by attainment of developmental milestones such as independent walking. Whether these associations persist across life is unknown. Therefore, we investigated associations between developmental milestones and spine shape, as determined using statistical shape models (SSMs) of lumbar spine from dual‐energy X‐ray absorptiometry scans in 1327 individuals (688 female) at 60 to 64 years in the MRC National Survey of Health and Development. Lumbar lordosis angle (L4 inferior endplate to T12 superior endplate) was measured using the two‐line Cobb method. In analyses adjusted for sex, height, lean and fat mass, socioeconomic position, and birthweight, later walking age was associated with greater lordosis described by SSM1 (regression coefficient, 0.023; 95% CI, 0.000‐0.047; P = .05) and direct angle measurement. Modest associations between walking age and less variation in anterior‐posterior vertebral size caudally (SSM6) were also observed (0.021; 95% CI, −0.002 to 0.044; P = .07). Sex interactions showed that later walking was associated with larger relative vertebral anterior‐posterior dimensions in men (SSM3; −0.043; 95% CI, −0.075 to 0.01; P = .01) but not women (0.018; 95% CI, −0.0007 to 0.043; P = .17). Similar associations were observed between age at independent standing and SSMs but there was little evidence of association between sitting age and spine shape. Unadjusted associations between walking age and SSMs 1 and 6 remained similar after adjustment for potential confounders and mediators. This suggests that these associations may be explained by altered mechanical loading of the spine during childhood growth, although other factors could contribute. Early life motor development, particularly walking, may have a lasting effect on the features of spine morphology with clinical significance.

Objectives Responsive biomarkers are needed to assess the progression of OA and their lack has hampered previous clinical trials. Statistical shape modelling (SSM) from radiographic images identifies those at greatest risk of fast-progression or joint replacement, but its sensitivity to change has not previously been measured. This study evaluates the responsiveness of SSM in knee OA in a 12-month observational study. Methods A total of 109 people were recruited who had undergone knee radiographs in the previous 12 months, and were grouped based on severity of radiographic OA (Kellgren–Lawrence grading). An SSM was built from three dual-energy X-ray absorptiometry scans at 6-month intervals. Change-over-time and OA were assessed using generalized estimating equations, standardized response means (SRM) and reliable change indices Results Mode 1 showed typical features of radiographic OA and had a strong link with Kellgren–Lawrence grading but did not change significantly during the study. Mode 3 showed asymmetrical changes consistent with medial cartilage loss, osteophytes and joint malalignment, and was responsive to change, with a 12-month SRM of 0.63. The greatest change was observed in the moderate radiographic OA group (SRM 0.92) compared with the controls (SRM 0.21), and the reliable change index identified 14% of this group whose progression was clinically significant. Conclusion Shape changes linked the progression of osteophytosis with increasing malalignment within the joint. Modelling of the whole joint enabled quantification of change beyond the point where bone-to-bone contact has been made. The knee SSM is, therefore, a responsive biomarker for radiographic change in knees over 12 months.

Objective Hip shape is a well-recognized risk factor for hip osteoarthritis (OA) and hip fracture. We aimed to investigate whether the genetic variants known to be associated with adult hip shape were also associated with adolescent hip shape. Methods Hip DXA scans, obtained in offspring from the Avon Longitudinal Study of Parents and Children (ALSPAC) at two time points (mean ages 13.8 and 17.8 years), were used to quantify hip morphology using a 53-point Statistical Shape Model (SSM). Principal component analysis was used to generate hip shape modes (HSMs). Genetic variants which had previously shown genome-wide significant association with specific HSMs in adults were tested for association with the same HSMs in adolescents (at each timepoint separately) using SNPTEST v2. Results Complete genotypic and phenotypic data were available for 3550 and 3175 individuals at 14 and 18 years, respectively. The strongest evidence for association with adolescent hip shape was for a variant located near SOX9 (rs2158915) with consistent effects across both time points for HSM1 (age 14: beta −0.05, p = 9.9 × 10−8; age 18: −0.05, p = 3.3 × 10−6) and HSM5 (age 14: beta −0.07, p = 1.6 × 10−4; age 18: −0.1, p = 2.7 × 10−6). There was also strong evidence of association between rs10743612 (near PTHLH) and HSM1 (age 14: 0.05, p = 1.1 × 10−5; age 18: 0.04, p = 0.003) and between rs6537291 (near HHIP) and HSM2 (age 14: −0.06, p = 0.001; age 18: −0.07, p = 0.001) across both time points. The genes with the strongest associations with hip shape in adolescents, (SOX9, PTHLH and HHIP) are known to be involved in endochondral bone formation. HSM1 indicates narrower aspect ratio of the upper femur, whereas both HSM2 and HSM5 reflect variation in the femoral head size and femoral neck width, features previously found to be related to the risk of OA in later life. The SOX9 locus has previously been found to associate with increased risk of hip fracture. Conclusion In conclusion, variants implicated in endochondral bone formation appear to consistently influence hip shape between adolescence and adulthood, including those aspects related to risk of hip OA and/or fracture in later life., Highlights • Genetic variants for adult hip shape are associated with DXA-derived hip shape in adolescents. • Genetic influences on hip shape are present as early as 14 years of age. • Variants implicated in endochondral bone formation may play a role in hip shape across lifespan.

Objective: The purpose of this study is to describe predictors of total hip replacement (THR) in community dwelling older adults. A better understanding of predictors of THR can aid in triaging patients and researching preventative strategies. Design: At baseline, participants had assessment of radiographic OA and cam morphology (from pelvic radiographs), shape mode scores and hip bone mineral density (BMD; from dual energy X-ray absorptiometry (DXA)). After 2.6 and 5 years, participants reported hip pain using WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index), and had hip structural changes assessed using magnetic resonance imaging (MRI). Risk of THR was analysed using mixed-effect Poisson regression. Results: Incidence of THR for OA over 14 years was 4.6% (37/801). As expected, WOMAC hip pain and hip radiographic OA both predicted risk of THR. Additionally, shape mode 2 score (decreasing acetabular coverage) (RR 1.83 per SD; 95% CI 1.1–3.04), shape mode 4 score (non-spherical femoral head) (RR 0.59/SD; 95% CI 0.36–0.96), cam morphology (α > 60°) (RR 2.2/SD; 95% CI 1.33–3.36), neck of femur BMD (RR 2.09/SD, 95% CI 1.48–2.94) and bone marrow lesions (BMLs) increased risk of THR (RR 7.10/unit; 95% CI 1.09–46.29). Conclusion: In addition to hip pain and radiographic hip OA, measures of hip shape, cam morphology, BMD and BMLs independently predict risk of THR. This supports the role of hip bone geometry and structure in the pathogenesis of end stage hip OA and has identified factors that can be used to improve prediction models for THR.

ObjectiveStatistical 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.MethodSSM 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.Results4,098 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 (β)-0.23;-0.33,-0.14) and 3D-HSM9 (β0.36; 0.27.0.45)], and CTM3 with 3D-HSMs describing cam morphology [3D-HSM3 (β-0.16;-0.25,-0.07) and 3D-HSM6 (β 0.19; 0.10.0.28)].ConclusionSubregional 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.

Considered for decades as a cartilage disease, recent studies of osteoarthritis (OA) take us back to the concepts discussed at the naming of the disorder as "bone-joint-inflammation". By describing the joint as an organ, can OA be called an organ disease - similar to heart disease? Is there a systemic (which system?) involvement? Would this help with diagnosis or therapy? Hyperplasia of the joint tissues is one of the most notable early features of the disease: articular cartilage thickens, chondrocytes proliferate and increase matrix biosynthesis, but not its incorporation; the subchondral bone densifies but is hypomineralised and there is an increase in bone marrow fat content. Associations between OA and hypertension, hypercholesterolaemia and blood glucose suggest systemic and metabolic components are involved. The source of pain is still unknown but here is evidence for peripheral and central sensitisation. Joint deformity is difficult to quantify, but statistical shape modelling provides a tool to use as an imaging biomarker. A genome-wide association study meta-analysis has identified novel genes associated with hip shape with many genes related to tissue growth and development. There are associations between hip shapes and age of first walking as well as with obesity through adulthood. These life-course events and a recapitulation in old age of developmental processes suggest that the cradle may affect our path to the grave. These observations suggest that tissue regeneration approaches, treating only the cartilage in OA joints, may only be of limited benefit.

Hip shape is an important determinant of hip osteoarthritis (OA), which occurs more commonly in women. However, it remains unclear to what extent differences in OA prevalence are attributed to sex differences in hip shape. Here, we explore sex differences in proximal femur shape in a cohort of adolescents. Hip morphology was quantified using hip DXA scans from the Avon Longitudinal Study of Parents and Children. Independent modes of variation (hip shape mode (HSM) scores) were generated for each image using an adult reference statistical shape model (N = 19,379). Linear regression was used to examine sex differences for the top ten HSMs, adjusting for age, height, lean and fat mass. Complete outcome and covariate data were available for 4,428 and 4,369 participants at ages 14 and 18 years, respectively. Several HSMs showed sex differences at both time points. The combined effect of sex on hip shape at age 14 reflected flatter femoral head and smaller lesser trochanter in females compared with males and, following adjustment for age and body size, these differences became more pronounced. At age 18, smaller lesser trochanter and femoral neck width (FNW) in females still remained although differences in femoral head, femoral shaft and FNW were largely attenuated following adjustment. Sexual dimorphism in proximal femur shape can be discerned in adolescence and early adulthood. Observed differences in proximal femur shape, particularly at age 14 were largely independent of body size, however to what extent differences in hip shape in early life play a role in predisposing to hip OA in later life remains to be determined.

© 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc. We aimed to report the first genomewide association study (GWAS) meta-analysis of dual-energy X-ray absorptiometry (DXA)-derived hip shape, which is thought to be related to the risk of both hip osteoarthritis and hip fracture. Ten hip shape modes (HSMs) were derived by statistical shape modeling using SHAPE software, from hip DXA scans in the Avon Longitudinal Study of Parents and Children (ALSPAC; adult females), TwinsUK (mixed sex), Framingham Osteoporosis Study (FOS; mixed), Osteoporotic Fractures in Men study (MrOS), and Study of Osteoporotic Fractures (SOF; females) (total N = 15,934). Associations were adjusted for age, sex, and ancestry. Five genomewide significant (p < 5 × 10−9, adjusted for 10 independent outcomes) single-nucleotide polymorphisms (SNPs) were associated with HSM1, and three SNPs with HSM2. One SNP, in high linkage disequilibrium with rs2158915 associated with HSM1, was associated with HSM5 at genomewide significance. In a look-up of previous GWASs, three of the identified SNPs were associated with hip osteoarthritis, one with hip fracture, and five with height. Seven SNPs were within 200 kb of genes involved in endochondral bone formation, namely SOX9, PTHrP, RUNX1, NKX3-2, FGFR4, DICER1, and HHIP. The SNP adjacent to DICER1 also showed osteoblast cis-regulatory activity of GSC, in which mutations have previously been reported to cause hip dysplasia. For three of the lead SNPs, SNPs in high LD (r2 > 0.5) were identified, which intersected with open chromatin sites as detected by ATAC-seq performed on embryonic mouse proximal femora. In conclusion, we identified eight SNPs independently associated with hip shape, most of which were associated with height and/or mapped close to endochondral bone formation genes, consistent with a contribution of processes involved in limb growth to hip shape and pathological sequelae. These findings raise the possibility that genetic studies of hip shape might help in understanding potential pathways involved in hip osteoarthritis and hip fracture. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link BACKGROUND: Oxidative stress (OS) negatively affects skeletal muscle homeostasis in experimental models of ageing. However, little is known about the associations between circulating OS markers and parameters of muscle mass and function, and their responses to exercise training, in humans. METHODS: Maximal voluntary contraction (MVC, primary outcome) and isokinetic torque of the knee extensors at 30° s-1 (MIT), muscle cross-sectional area (MCSA) and quality (MQ, secondary outcomes), and plasma concentrations of malondialdehyde (MDA, pro-OS), homocysteine (HCY, pro-OS), taurine (TAU, anti-OS), and protein sulphydryl groups (PSH, anti-OS) were measured in 27 healthy older males and 23 females at baseline and after an 18-week resistance exercise program, with or without a nutritional intervention (fish oil vs. placebo). RESULTS: After adjusting for age, glomerular filtration rate, and nutritional intervention, there were no significant correlations between baseline OS markers and muscle parameters, barring a positive association between TAU and MIT in females (r = 0.53, P = .035) and between MDA and MCSA in males (r = 0.69, P = .001). Training did not significantly change OS markers, except for a reduction in MDA in females (-0.27 μmol/L, 95% CI -0.51 to -0.02, P = .034). In females, there were significant correlations between baseline MDA and exercise-induced changes in MVC (P = .018), baseline TAU and changes in MCSA (P = .026), and baseline HCY and changes in MCSA (P = .046) and MQ (P = .022). In males, baseline MDA was significantly associated with exercise-induced changes in MVC (P = .040). CONCLUSIONS: Plasma MDA, HCY, and TAU were significantly associated with baseline and/or exercise-induced changes in muscle mass and function in healthy older adults, primarily in females. Pending further confirmation in other populations, specific OS markers, particularly MDA, might predict muscle responses to resistance exercise programs in old age.

Objective It remains unclear how the different features of radiographic hip osteoarthritis (rHOA) contribute to hip pain. We examined the relationship between rHOA, including its individual components, and hip pain using a novel dual-energy x-ray absorptiometry (DXA)-based method. Methods Hip DXAs were obtained from UK Biobank. A novel automated method obtained minimum joint space width (mJSW) from points placed around the femoral head and acetabulum. Osteophyte areas at the lateral acetabulum, superior and inferior femoral head were derived manually. Semi-quantitative measures of osteophytes and joint space narrowing (JSN) were combined to define rHOA. Logistic regression was used to examine the relationships between these variables and hip pain, obtained via questionnaires. Results 6807 hip DXAs were examined. rHOA was present in 353 (5.2%) individuals and was associated with hip pain [OR 2.42 (1.78–3.29)] and hospital diagnosed OA [6.01 (2.98–12.16)]. Total osteophyte area but not mJSW was associated with hip pain in mutually adjusted models [1.31 (1.23–1.39), 0.95 (0.87–1.04) respectively]. On the other hand, JSN as a categorical variable showed weak associations between grade ≥ 1 and grade ≥ 2 JSN with hip pain [1.30 (1.06–1.60), 1.80 (1.34–2.42) respectively]. Acetabular, superior and inferior femoral osteophyte areas were all independently associated with hip pain [1.13 (1.06–1.20), 1.13 (1.05–1.24), 1.10 (1.03–1.17) respectively]. Conclusion In this cohort, the relationship between rHOA and prevalent hip pain was explained by 2-dimensional osteophyte area, but not by the apparent mJSW. Osteophytes at different locations showed important, potentially independent, associations with hip pain, possibly reflecting the contribution of distinct biomechanical pathways., Highlights • Radiographic hip OA, derived from DXA images, is associated with hip pain in UK Biobank. • Osteophyte size, as reflected by osteophyte area on the DXA image, shows strong associations with hip pain. • In contrast, joint space width is only weakly associated with hip pain.

Objective Hip morphology plays a significant role in the incidence and progression of hip osteoarthritis (OA). We hypothesized that hip shape would also be associated with other key factors and tested this in a longitudinal community-based cohort combining radiographic, magnetic resonance imaging (MRI), dual-energy x-ray absorptiometry (DXA), and clinical data. Methods Baseline DXA images of the left hip of 831 subjects from the Tasmanian Older Adult Cohort were analyzed using an 85-point statistical shape model. Hip pain was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index, and muscle strength was measured using a dynamometer. Hip structural changes were assessed using MRI and radiographic OA using plain radiographs. Results Six shape modes accounted for 68% of shape variation. At baseline, modes 1, 2, 4, and 6 were associated with radiographic hip OA; modes 1, 3, 4, and 6 were correlated with hip cartilage volume; and all except mode 2 were correlated with muscle strength. Higher mode 1 and lower mode 3 and mode 6 scores at baseline predicted hip pain at followup and higher mode 1 and mode 2 scores were associated with hip effusion-synovitis. Higher scores for mode 2 (decreasing acetabular coverage) and lower scores for mode 4 (nonspherical femoral head) at baseline predicted 10-year total hip replacement (THR), while mode 4 alone was correlated with bone marrow lesions (BMLs), effusion-synovitis, and increased cartilage signal. Conclusion Hip shape is associated with radiographic OA, THR, hip pain, effusion-synovitis, BMLs, muscle strength, and hip structural changes. These data suggest that different shape modes reflect multiple facets of hip OA.

Background Injury is an important risk factor for osteoarthritis (OA), a highly prevalent and disabling joint disease. Joint shape is linked to OA, but the interplay of injury and joint shape and their combined role in OA, particularly at the ankle, is not well known. Therefore, we explored cross-sectional associations between ankle shape and injury in a large community-based cohort. Methods Ankles without radiographic OA were selected from the current data collection of the Johnston County OA Project. Ankles with self-reported prior injury were included as injury cases (n = 108) along with 1:1 randomly selected non-injured ankles. To define ankle shape, a 68 point model on weight-bearing lateral ankle radiographs was entered into a statistical shape model, producing a mean shape and a set of continuous variables (modes) representing variation in that shape. Nineteen modes, explaining 80% of shape variance, were simultaneously included in a logistic regression model with injury status as the dependent variable, adjusted for intra-person correlation, sex, race, body mass index (BMI), baseline OA radiographic grade, and baseline symptoms. Results A total of 194 participants (213 ankles) were included; mean age 71 years, BMI 30 kg/m2, 67% white and 71% women. Injured ankles were more often symptomatic and from whites. In a model adjusted only for intra-person correlation, associations were seen between injury status and modes 1, 6, 13, and 19. In a fully adjusted model, race strongly affected the estimate for mode 1 (which was no longer statistically significant). Conclusions This study showed variations in ankle shape and history of injury as well as with race. These novel findings may indicate a change in ankle morphology following injury, or that ankle morphology predisposes to injury, and suggest that ankle shape is a potentially important factor in the development of ankle OA.

Objective To examine the relationship between pubertal timing (using measures of height tempo) and proximal femur shape in a large adolescent cohort. Methods Hip DXA scans were obtained in offspring from the Avon Longitudinal Study of Parents and Children. To quantify hip morphology, the images were analyzed using Shape software based on a 53-point statistical shape model and independent modes of variation (hip shape mode (HSM) scores) for each image were generated. Height tempo (which corresponds to age at peak height velocity (aPHV)) was estimated from serial height measurements collected between age 5–20 years. Multivariable linear regression was used to examine cross-sectional associations between height tempo and the top ten HSMs at age 14 and 18, adjusting for sex and fat mass index (FMI). Results Complete outcome and covariate data were available from 3827 and 3507 participants at age 14 and 18 years, respectively. Mean aPHV was 13.5 and 11.8 years for males and females, respectively. At age 14, height tempo was associated with a majority of modes, except for HSM4 and there was strong evidence of interaction by sex. In males, all modes showed evidence of an association with tempo, independent of FMI, with the strongest observed for HSM8 (adjusted β 0.38 (0.33, 0.43) p = 4.1 × 10−50). Compared with males, the associations were generally weaker in females, with the strongest effect observed for HSM8 (adjusted β 0.10 (0.05, 0.14) p = 1.6 × 10−5). The overall effect of later pubertal timing on proximal femur shape in males was a narrower femoral neck and larger superolateral head, whereas in females these changes were hard to discern. When assessed at age 18, there was little relationship between tempo and proximal femur shape in either sex. Conclusion Our results indicate that significant changes in hip shape occur during puberty, including aspects of shape which may be related to future risk of hip OA and/or fracture. However, puberty timing per se does not appear to exert long lasting effects on proximal femur shape., Highlights • Puberty represents an important period for the development of hip shape. • Associations between pubertal timing and hip shape at age 14 were stronger in males. • Pubertal timing does not appear to have lasting effects on hip shape.

Background: Lumbar disc degeneration (LDD) is a condition associated with recurrent low back pain (LBP). Knowledge regarding effective management is limited. As a step towards the identification of risk, prognostic or potentially modifiable factors in LDD patients, the aim of this study was to explore the hypothesis that intrinsic lumbar spine shape is associated with LDD and clinical outcomes in symptomatic adults. Methods: 3 T MRI was used to acquire T2-weighted sagittal images (L1-S1) from 70 healthy controls and LDD patients (mean age 49 years, SD 11, range 31-71 years). Statistical Shape Modelling (SSM) was used to describe lumbar spine shape. SSM identified variations in lumbar shape as 'modes' of variation and quantified deviation from the mean. Intrinsic shape differences were determined between LDD groups using analysis of variance with post-hoc comparisons. The relationship between intrinsic shape and self-reported function, mental health and quality of life were also examined. Results: The first 7 modes of variation explained 91% of variance in lumbar shape. Higher LDD sum scores correlated with a larger lumbar lordosis (Mode 1 (55% variance), P = 0.02), even lumbar curve distribution (Mode 2 (12% variance), P = 0.05), larger anterior-posterior (A-P) vertebral diameter (Mode 3 (10% variance), P = 0.007) and smaller L4-S1 disc spaces (Mode 7 (2% variance), P ≤ 0.001). In the presence of recurrent LBP, LDD was associated with a larger A-P vertebral diameter (Mode 3) and a more even lumbar curvature with smaller L5/S1 disc spaces (Mode 4), which was significantly associated with patient quality of life (P = 0.002-0.04, rp = 0.43-0.61)). Conclusions: This exploratory study provides new evidence that intrinsic shape phenotypes are associated with LDD and quality of life in patients. Longitudinal studies are required to establish the potential role of these risk or prognostic shape phenotypes.

Grant support This study was supported by an award (Ref: WHMSB-AU119) from the Translational Medicine Research Collaboration – a consortium made up of the Universities of Aberdeen, Dundee, Edinburgh and Glasgow, the four associated NHS Health Boards (Grampian, Tayside, Lothian and Greater Glasgow & Clyde), Scottish Enterprise and Wyeth. The funder played no part in the design, execution, analysis or publication of this paper. Acknowledgements We are grateful to Mrs D. Younie for kindly arranging the imaging sessions and Mrs B.MacLennan (research radiographer) for acquiring the MR images. We also thank Dr S. Galea-Soler, Dr G. Waiter, Dr.Zhiqing Wu, and Dr K. Yoshida for Kellgren-Lawrence grading, help and advice, and Mr G. Buchan for his expertise making the phantoms.

Objective.Hip shape by statistical shape modeling (SSM) is associated with hip radiographic osteoarthritis (rOA). We examined associations between hip shape and knee rOA given the biomechanical interrelationships between these joints.Methods.Bilateral baseline hip shape assessments [for those with at least 1 hip with a Kellgren-Lawrence arthritis grading scale (KL) 0 or 1] from the Johnston County Osteoarthritis Project were available. Proximal femur shape was defined on baseline pelvis radiographs and evaluated by SSM, producing mean shape and continuous variables representing independent modes of variation (14 modes = 95% of shape variance). Outcomes included prevalent [baseline KL ≥ 2 or total knee replacement (TKR)], incident (baseline KL 0/1 with followup ≥ 2), and progressive knee rOA (KL increase of ≥ 1 or TKR). Limb-based logistic regression models for ipsilateral and contralateral comparisons were adjusted for age, sex, race, body mass index (BMI), and hip rOA, accounting for intraperson correlations.Results.We evaluated 681 hips and 682 knees from 342 individuals (61% women, 83% white, mean age 62 yrs, BMI 29 kg/m2). Ninety-nine knees (15%) had prevalent rOA (4 knees with TKR). Lower modes 2 and 3 scores were associated with ipsilateral prevalent knee rOA, and only lower mode 3 scores were associated with contralateral prevalent knee rOA. No statistically significant associations were seen for incident or progressive knee rOA.Conclusion.Variations in hip shape were associated with prevalent, but not incident or progressive, knee rOA in this cohort, and may reflect biomechanical differences between limbs, genetic influences, or common factors related to both hip shape and knee rOA.

Concerns have been raised that deformation of acetabular shells may disrupt the assembly process of modular prostheses. In this study we aimed to examine the effect that the strength of bone has on the amount of deformation of the acetabular shell. The hypothesis was that stronger bone would result in greater deformation. A total of 17 acetabular shells were inserted into the acetabula of eight cadavers, and deformation was measured using an optical measuring system. Cores of bone from the femoral head were taken from each cadaver and compressed using a materials testing machine. The highest peak modulus and yield stress for each cadaver were used to represent the strength of the bone and compared with the values for the deformation and the surgeon’s subjective assessment of the hardness of the bone. The mean deformation of the shell was 129 µm (3 to 340). No correlation was found between deformation and either the maximum peak modulus (r² = 0.011, t = 0.426, p = 0.676) or the yield stress (r² = 0.024, t = 0.614, p = 0.549) of the bone. Although no correlation was found between the strength of the bone and deformation, the values for the deformation observed could be sufficient to disrupt the assembly process of modular acetabular components. Cite this article: Bone Joint J 2015; 97-B:473–7.

Magnetic resonance imaging (MRI) was used to investigate muscle rehabilitation following cast immobilization. The aim was to explore MRI as an imaging biomarker of muscle function. Sixteen patients completed an eight-week rehabilitation programme following six weeks of cast immobilization for an ankle fracture. MRI of the lower leg was performed at two-week intervals for 14 weeks. Total volume and anatomical cross-sectional areas at 70% of the distance from lateral malleolus to tibial tuberosity (ACSA) were measured for tibialis anterior (TA), medial and lateral gastrocnemius (GM and GL) and soleus (SOL). Pennation angle of muscle fascicules was measured at the same position in GM. Fractional fat/water contents and T2 relaxation times before and after exercise were calculated. Strength was measured as maximum isometric torque developed in plantar- and dorsi-flexion. Torque increased by (mean [SD]) 1.10 (0.32) N m day−1 in males, 0.74 (0.43) N m day−1 in females in plantar-flexion (0.9% of final strength p...

Objective To examine relationships between known osteoarthritis (OA) susceptibility loci and hip shape in a population-based cohort of perimenopausal women in order to investigate whether hip shape contributes to OA development. Methods Hip shape was measured, using statistical shape modeling, on dual x-ray absorptiometry scans of the hip from mothers in the Avon Longitudinal Study of Parents and Children (ALSPAC). The proximal femur and superior acetabulum were outlined, and independent hip shape modes were generated. In a subregional model, points were restricted to the acetabulum and superior femoral head. Associations between 11 OA-related single-nucleotide polymorphisms, identified by literature search, and shape modes were analyzed in a multivariate canonical correlation analysis. Results A total of 3,111 women (mean age 48 years) had genetic and hip shape data. The KLHDC5/PTHLH rs10492367 OA risk allele was associated with a wider upper femur in the whole shape model (P = 1 × 10-5 ). The DOT1L rs12982744 OA risk allele was associated with reduced superior joint space in the subregional shape model (P = 2 × 10-3 ). The COL11A1 rs4907986 OA risk allele was associated with lateral displacement of the femoral head relative to the acetabulum in the subregional shape model (P = 5 × 10-4 ). Regional association plots identified an additional COL11A1 locus in moderate linkage disequilibrium with rs4907986, which was more strongly associated with hip shape (rs10047217; P = 3 × 10-6 ). Colocalization analysis indicated sharing of genetic signals for hip shape and hip OA for the KLHDC5/PTHLH and COL11A1 loci. Conclusion Hip OA susceptibility loci were associated with shape in this study, suggesting that these loci (and potentially yet-to-be-identified hip OA loci) could contribute to hip OA in later life via perturbing biologic pathways that mediate morphology development.

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link. Objectives The current study was designed to explore the associations between L-arginine metabolites and muscle mass and function in old age, which are largely unknown. Design The study used a randomised, double-blind, placebo-controlled design. Setting The study was carried out in a laboratory setting. Participants 50 healthy older adults [median age 70 years (IQR 67-73); 27 males]. Intervention Participants undertook an 18-week resistance exercise program, and a nutritional intervention (fish oil vs. placebo). Measurements Serum homoarginine, ornithine, citrulline, asymmetric dimethylarginine (ADMA), NG-monomethyl-L-arginine (L-NMMA), and symmetric dimethylarginine (SDMA), maximal voluntary contraction (MVC) and isokinetic torque of the knee extensors at 30° s-1 (MIT), muscle cross sectional area (MCSA) and quality (MQ) were measured at baseline and after the intervention. Results No significant exercise-induced changes were observed in metabolite concentrations. There were significant sex differences in the associations between metabolites and muscle parameters. After adjusting for age, glomerular filtration rate and fish oil intervention, citrulline (P=0.002) and ornithine (P=0.022) were negatively associated with MCSA at baseline in males but not females. However, baseline citrulline was negatively correlated with exercise-induced changes in MVC (P=0.043) and MQ (P=0.026) amongst females. Furthermore, amongst males, baseline homoarginine was positively associated with exercise-induced changes in MVC (P=0.026), ADMA was negatively associated with changes in MIT (P=0.026), L-NMMA (p=0.048) and ornithine (P

Predicting who will develop osteoarthritis, assessing how rapidly their disease will progress and monitoring early responses to treatment are key to the development of therapeutic agents able to treat this crippling disease and to their future clinical use. Statistical Shape Modelling (SSM) enables quantification of variations in multiple geometric measures describing the whole hip joint to be considered in concert. This prospective study evaluates the responsiveness of SSM to changes in hip-shape within 1 year.Sixty-two people, mean age 67.1 yrs, were recruited. Dual-energy X-ray Absorptiometry images were taken at three timepoints (baseline, 6 and 12 months). Based on Kellgren-Lawrence grading (KLG) of their baseline images, subjects were classified into control/doubtful OA: KLG 1 in both hips; moderate OA: KLG = 2; and severe OA: KLG ≥ 3 in their most severe hip. Morphology was quantified using SSM and changes in shape were assessed using generalised estimating equations. Standardized response means (SRMs) were calculated for the first and second 6 month periods, then the full 12 months.Disease severity ranged from KLG0-KLG4 in the 124 hips assessed at baseline. Three SSM modes (Modes 1, 3 and 4) were associated with OA severity. Across the whole cohort, SRM magnitudes ranged from 0.16 to 0.63. The greatest subgroup SRM (magnitude 0.91) was observed over 12 months in those subjects with moderate OA (KLG2).We have demonstrated that SSM can capture changes in hip shape over 6 and 12 months across the entire hip joint providing a sensitive measure of hip OA progression.

The objectives of the present study were to determine ( 1 ) whether differences in the radiographic appearance of the of the proximal femoral canal exist on corresponding AP pelvis and AP hip radiographs, and ( 2 ) whether radiographic assessment of canal shape is accurate with reference to computed tomography (CT). In a retrospective study, corresponding radiographs and CT scans of 100 consecutive patients with primary hip OA were evaluated. Active shape modelling (ASM) was performed to assess the variation in proximal femoral canal shape and to identify differences between AP hip and AP pelvis views. Differences in the medial cortical flare between radiographs and CT were quantified using least squares curve fitting. ASM identified significant differences in the assessment of canal shape on corresponding AP hip and AP pelvis views. Curve fitting demonstrated a good agreement between AP hip radiographs and CT. Agreement between AP pelvis radiographs and CT was less good. In contrast to AP pelvis radiographs, AP hip radiographs allow a more accurate and reliable assessment of proximal femoral canal shape in the frontal plane in primary hip OA. Our findings may improve stem fit in total hip arthroplasty without the routine use of CT.

Purpose There is a continuing need to improve the prediction of hip fractures to identify those at highest risk, enabling cost-effective use of preventative therapies. Methods The aim of this work was to validate an innovative imaging biomarker for hip fracture by modelling the shape and texture of the proximal femur assessed from dual energy X-ray absorptiometry (DXA) scans. Scans used were acquired at baseline from elderly patients participating in a prospective, placebo-controlled fracture prevention study of the bisphosphonate, clodronate. 182 subjects who subsequently suffered a hip fracture were age, weight and height matched with two controls who did not suffer a fracture during a median 4-year follow-up period. Logistic regression was used to test if variables were good predictors of fracture and adjust for bone mineral density (BMD). Results Shape mode 2, reflecting variability in neck-shaft angle, neck width and the size of both trochanters (0.81 (OR), 0.68–0.97 (CI), 0.024 ( P )), and appearance mode 6, recording grey-level contrast (1.33, 1.11–1.59, 0.002), were significant predictors of hip fracture and remained so after adjustment for BMD (shape mode 2 (0.77, 0.64–0.93, 0.006), appearance mode 6 (1.32, 1.10–1.59, 0.003)). Receiver Operating Curve analysis showed the combination of shape mode 2, appearance mode 6 and BMD was 3% better than any single predictor. Conclusion Variables derived from shape and appearance models gave a prediction of fracture comparable to BMD and in combination with BMD gave an improvement in the prediction of hip fracture that could predict an additional 2000 hip fracture cases per year in the UK, potentially saving more than £20 million per year and 10,000 cases in the US.

The anatomical shape of bones and joints is important for their proper function but quantifying this, and detecting pathological variations, is difficult to do. Numerical descriptions would also enable correlations between joint shapes to be explored. Statistical shape modelling (SSM) is a method of image analysis employing pattern recognition statistics to describe and quantify such shapes from images; it uses principal components analysis to generate modes of variation describing each image in terms of a set of numerical scores after removing global size variation. We used SSM to quantify the shapes of the hip and the lumbar spine in dual‐energy x‐ray absorptiometry (DXA) images from 1511 individuals in the MRC National Survey of Health and Development at ages 60–64 years. We compared shapes of both joints in men and women and hypothesised that hip and spine shape would be strongly correlated. We also investigated associations with height, weight, body mass index (BMI) and local (hip or lumber spine) bone mineral density. In the hip, all except one of the first 10 modes differed between men and women. Men had a wider femoral neck, smaller neck‐shaft angle, increased presence of osteophytes and a loss of the femoral head/neck curvature compared with women. Women presented with a flattening of the femoral head and greater acetabular coverage of the femoral head. Greater weight was associated with a shorter, wider femoral neck and larger greater and lesser trochanters. Taller height was accompanied by a flattening of the curve between superior head and neck and a larger lesser trochanter. Four of the first eight modes describing lumbar spine shape differed between men and women. Women tended to have a more lordotic spine than men with relatively smaller but caudally increasing anterior‐posterior (a‐p) vertebral diameters. Men were more likely to have a straighter spine with larger vertebral a‐p diameters relative to vertebral height than women, increasing cranially. A weak correlation was found between body weight and a‐p vertebral diameter. No correlations were found between shape modes and height in men, whereas in women there was a weak positive correlation between height and evenness of spinal curvature. Linear relationships between hip and spine shapes were weak and inconsistent in both sexes, thereby offering little support for our hypothesis. In conclusion, men and women entering their seventh decade have small but statistically significant differences in the shapes of their hips and their spines. Associations with height, weight, BMI and BMD are small and correspond to subtle variations whose anatomical significance is not yet clear. Correlations between hip and spine shapes are small.

Background: Resistance exercise increases muscle mass and function in older adults, but responses are attenuated compared with younger people. Data suggest that long-chain n–3 polyunsaturated fatty acids (PUFAs) may enhance adaptations to resistance exercise in older women. To our knowledge, this possibility has not been investigated in men. Objective: We sought to determine the effects of long-chain n–3 PUFA supplementation on resistance exercise training–induced increases in muscle mass and function and whether these effects differ between older men and women. Design: Fifty men and women [men:n= 27, mean ± SD age: 70.6 ± 4.5 y, mean ± SD body mass index (BMI; in kg/m2): 25.6 ± 4.2; women:n= 23, mean ± SD age: 70.7 ± 3.3 y, mean ± SD BMI: 25.3 ± 4.7] were randomly assigned to either long-chain n–3 PUFA (n= 23; 3 g fish oil/d) or placebo (n= 27; 3 g safflower oil/d) and participated in lower-limb resistance exercise training twice weekly for 18 wk. Muscle size, strength, and quality (strength per unit muscle area), functional abilities, and circulating metabolic and inflammatory markers were measured before and after the intervention. Results: Maximal isometric torque increased after exercise training to a greater (P 0.05) between groups in men. In both sexes, the effect of exercise training on maximal isokinetic torque at 30, 90, and 240° s−1, 4-m walk time, chair-rise time, muscle anatomic cross-sectional area, and muscle fat did not differ (P >0.05) between groups. There was a greater (P 0.05). Long-chain n–3 PUFAs resulted in a greater decrease (P 0.05) in glucose, insulin, or inflammatory markers. Conclusion: Long-chain n–3 PUFA supplementation augments increases in muscle function and quality in older women but not in older men after resistance exercise training. This trial was registered at clinicaltrials.gov as NCT02843009.

Introduction The geometrical shape of the proximal femur has previously been shown to predict primary hip fractures. Hip fractures are routinely diagnosed on plain radiographs of the pelvis, and these have both hips viewable. We have investigated if statistical shape modelling of the uninvolved hip on plain radiographs, at the time of the first hip fracture episode, could predict a subsequent ‘second fracture’ on that (uninvolved) side. Materials and methods 60 radiographs taken at the time of the index hip fracture were blinded and separated into two arms; patients sustaining one hip fracture only (n = 30), and those who went on to sustain a second fracture (n = 30), over the three-year follow-up period. Two separate shape models were used for these groups and compared using t-tests or Mann–Whitney U-tests, along with Cohen's d to measure the effect size of each measure. Results We found no statistically significant difference in the shape of the femur between the first fracture and second fracture group (p > 0.05) and no results reached a “medium” effect size (Cohen's d Conclusions Shape modelling is feasible and can be applied in the routine clinical setting. However, we were unable to elucidate any predictive value in this relatively small sample. A reliable radiograph-based method of identifying patients at risk of second fracture would be of value in planning prevention, service provision, and cost analysis. Further work is required and a study with more patients might exclude the type 2 error in our work.

Objective. Previously, active shape modelling (ASM) of the proximal femur was shown to identify those individuals at highest risk of developing radiographic OA. Here we determine whether ASM predicts the need for total hip replacement (THR) independent of KellgrenLawrence grade (KLG) and other known risk factors. Methods. A retrospective cohort study of 141 subjects consulting primary care with new hip pain was conducted. Pelvic radiographs taken on recruitment were assessed for KLG, centre-edge angle, acetabular depth and femoral head migration. Clinical factors (duration of pain, use of a stick and physical function) were collected by self-completed questionnaires. ASM differences between shape mode scores at baseline for individuals who underwent THR during the 5-year follow-up (n = 27) and those whose OA did not progress radiographically (n = 75) were compared. Results. A1 S.D. reduction in baseline ASM mode 2 score was associated with an 81% reduction in odds of THR (OR = 0.19, 95% CI 0.52, 0.70) after adjustment for KLG, radiographic and clinical factors. A similar reduction in odds of THR was associated with a 1 S.D. reduction in mode 3 (OR = 0.45, 95% CI 0.28, 0.71) and a 1 S.D. increase in mode 4 score (OR = 2.8, 95% CI 1.7, 4.7), although these associations were no longer significant after adjustment for KLG and clinical factors. Conclusion. ASM of the hip joint is a reliable early biomarker of radiographic OA severity, which can improve the ability to identify patients at higher risk of rapid progression and poor outcome even when KLG and clinical risk factors are taken into account.

Purpose: To investigate MRI biomarkers of muscle atrophy during cast immobilization of the lower leg. Materials and Methods: Eighteen patients (8 male, 10 female), who had one lower leg immobilized in a cast, underwent 3.0 Tesla (T) MR imaging 5, 8, 15, 29, and 43 days after casting. Measurements were made on both lower legs of total muscle volume. Cross-sectional area (CSA), fractional water content, and T2 were measured in tibialis anterior (TA), gastrocnemius medialis (GM) and lateralis (GL) and soleus (SOL). Fiber pennation angle was measured in GM. Results: Total muscle volume decreased by 17% (P < 0.001) over the 6 weeks of immobilization. The greatest loss in CSA (mean[SD]) was seen in GM (−23.3(8.7)%), followed by SOL (−19.0(9.8)%), GL (−17.1(6.5)%), and TA (−10.7(5.9)%). Significant reductions of CSA were also detectable in the contra-lateral leg. T2 increased in all muscles: TA 27.0(2.5) ms to 29.6(2.8) ms (P < 0.001), GM 34.6(2.9) ms to 39.8(5.4) ms (P < 0.001) and SOL 34.4 (2.9) ms to 44.9(5.9) ms (P < 0.001). Small reductions were found in fractional water content. Pennation angle decreased in the cast leg (P < 0.001). Conclusion: Quantitative MR imaging can detect and monitor progressive biochemical and biophysical changes in muscle during immobilization. J. Magn. Reson. Imaging 2012;35:686-695. © 2011 Wiley Periodicals, Inc.

Rupture of the anterior cruciate ligament is common and may necessitate surgical reconstruction. Surgical reconstruction aims to restore normal kinematics and biology within the knee. The acute phase response after surgical reconstruction remains poorly defined but may influence graft integration through modulation of host tissue remodelling. The very early host production of key cytokines after surgery was studied. A consecutive series of 14 patients undergoing reconstructive surgery were studied per-operatively, 1 and 6 h after surgery, examining the hypothesis that the acute phase response would be non-specific but consistent between individuals, demonstrating increases of pro-inflammatory cytokines. A consistent increased release of monocyte-driven, non-specific, IL-1 and IL-6 release but not T cell-derived IL-2 was found. Perhaps, more interestingly, very early high concentrations of secondary growth factors PDGF and TGF-β suggestive of an anabolic response were found. These data support the contention that an anabolic response starts earlier than previously thought within the surgically reconstructed knee.

Arthritis Research UK published a report in 2009 entitled "Osteoarthritis and obesity" in which they highlight the severe consequences of obesity for musculoskeletal health. Throughout the report, however, the mechanical effect of excess body weight is assumed to be the direct cause of osteoarthritis (OA). Although this assumption is common, is it supported by the evidence? A survey of the studies associating OA with obesity is inconclusive on whether body weight is the causative factor. The increase in direct-loading on joints due to weight-gain is not as great as is often believed, and compensatory gait patterns ameliorate much of the kinematic effects. One manifestation of obesity, however, is increased adipose tissue--a rich source of proinflammatory endocrine factors. I propose that body weight might not be the main problem in OA pathogenesis, but that increased adipose tissue itself might be both an indicator and a driver of widespread disease.

The shape of the lumbar spine in the sagittal plane varies between individuals and as a result of postural changes but it is not known how the shape in different postures is related. Sagittal images of the lumbar spines of 24 male volunteers were acquired using a positional magnetic resonance scanner. The subjects were imaged lying supine, standing and sitting. An active shape model was used to characterize shape in terms of independent modes of variation. Two modes were identified that described the total (mode 1) and distribution (mode 2) of the curvature. The spinal shape was found to be intercorrelated between the three postures for both modes, suggesting that the lumbar spine has an element of shape that is partially maintained despite postural alterations. Mode 1 values indicated that the spine was straightest when standing and curviest when sitting. Mode 2 values indicated that the distribution in the curvature was most even when sitting and least even when lying supine. Systematic differences in the behaviour of the spine, when changing posture, were found that suggest that the shape of the spine may affect its biomechanics.

The traditional view of OA is that it is primarily a disease of articular cartilage that results, by altering the biomechanics of the joint, in secondary changes to the subchondral bone and, through secondary inflammation, other joint tissues. This focus on cartilage tends to ignore other musculoskeletal changes reported, especially those remote from affected joints. It has been proposed instead that generalized OA is a systemic musculoskeletal disorder with a metabolic component. Evidence for this position will be presented by summarizing changes identified in all the major musculoskeletal tissues. This will endeavour to show the links between these tissues, most of which have a common mesenchymal origin. Dysregulated tissue turnover, with the balance in favour of growth, will be seen to be a common thread underlying many of the changes described. It is proposed that the production of new tissue in the midst of existing tissue, in the wrong place and at the wrong time, could result in the changes observed and that reversion of cellular behaviour to an earlier, developmental-like, phenotype may provide a mechanism that could drive the disease process. New therapies may arise both from recognizing this whole musculoskeletal disease phenotype and by exploring what might be the factors underlying this cellular reversion.

Cnr2 is one of two cannabinoid receptors known to regulate bone metabolism. Here, we compared the whole bone properties of femora and tibiae from three-month-old Cnr2−/- mice with wild-type controls using a C57BL/6 background. Bending stiffness was measured by three-point bending. The elastic modulus, density and mineral content were measured using ultrasound, Archimedes’ principle and ashing. Micro-CT was used to measure the second moment of area, inner and outer perimeters of the cortical shaft and trabecular parameters. Deleting Cnr2 increased the bending stiffness by increasing the second moment of area. Bone from affected male mice had a greater modulus than controls, although no difference was observed in females. The fractional volume of trabecular bone was greater in Cnr2−/- females than controls, while no difference was seen in males. These data indicate that inactivating Cnr2 increases the amount of cortical bone in both males and females at 3 months of age, but the effect on trabecular bone is different in the two sexes. These findings extend previous studies looking only at trabecular bone and provide further support for the possible use of Cnr2 antagonists for improving bone properties that may be of value in the treatment of bone disorders.

This article compares and combines methods for examining the external shape and the internal structure of the proximal femur with bone mineral density (BMD) to provide a classifier for hip fracture.Fifty standard pelvic radiographs were available from age-matched fracture and control groups of postmenopausal women. Femoral shape was measured using an active shape model, the trabecular structure by means of a Fourier transform.Both the shape and various structure measures were independent of BMD (P=0.16 and0.50, respectively). Calculating the area under the receiver operator characteristic (ROC) curve (Az), each of shape (Az=0.81), the best structure measure (Az=0.79-0.93), and BMD (Az=0.79), could partially classify the fracture and control groups. However, the combination achieved almost perfect separation (Az=0.99).This pilot study shows how bone shape and structure can complement BMD measurements for investigations of fracture risk.