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Objective: To examine the genetic architecture of cam morphology using alpha angle (AA) as a proxy measure and conduct an AA genome-wide association study (GWAS) followed by Mendelian randomization (MR) to evaluate its causal relationship with hip osteoarthritis (OA). Methods: Observational analyses examined associations between AA measurements derived from hip dual x-ray absorptiometry (DXA) scans from the UK Biobank study and radiographic hip OA outcomes and subsequent total hip replacement. Following these analyses, an AA GWAS meta-analysis was performed (N = 44,214) using AA measurements previously derived in the Rotterdam Study. Linkage disequilibrium score regression assessed the genetic correlation between AA and hip OA. Genetic associations considered significant (P < 5 × 10−8) were used as AA genetic instrument for 2-sample MR analysis. Results: DXA-derived AA showed expected associations between AA and radiographic hip OA (adjusted odds ratio [OR] 1.63 [95% confidence interval (95% CI) 1.58, 1.67]) and between AA and total hip replacement (adjusted hazard ratio 1.45 [95% CI 1.33, 1.59]) in the UK Biobank study cohort. The heritability of AA was 10%, and AA had a moderate genetic correlation with hip OA (rg = 0.26 [95% CI 0.10, 0.43]). Eight independent genetic signals were associated with AA. Two-sample MR provided weak evidence of causal effects of AA on hip OA risk (inverse variance weighted OR 1.84 [95% CI 1.14, 2.96], P = 0.01). In contrast, genetic predisposition for hip OA had stronger evidence of a causal effect on increased AA (inverse variance weighted β = 0.09 [95% CI 0.04, 0.13], P = 4.58 × 10−5). Conclusion: Expected observational associations between AA and related clinical outcomes provided face validity for the DXA-derived AA measurements. Evidence of bidirectional associations between AA and hip OA, particularly for risk of hip OA on AA, suggests that hip shape modeling secondary to a genetic predisposition to hip OA contributes to the well-established relationship between hip OA and cam morphology in older adults.

ObjectiveMinimum joint space width (mJSW) from 2-dimensional images provides a proxy for cartilage thickness. This study aimed to conduct a genome-wide association study (GWAS) of mJSW to (i) identify new genetic determinants of mJSW and use them to (ii) examine causal effects of mJSW on hip osteoarthritis (HOA) risk.MethodsGWAS meta-analysis of hip mJSW derived from plain X-rays (four cohorts) or DXA (one cohort) was performed, stratified by sex and adjusted for age and ancestry principal components. Mendelian randomisation (MR) and cluster analyses were used to examine causal effect of mJSW on HOA.Results50,745 individuals were included in the meta-analysis. 42 SNPs, which mapped to 39 loci (35 novel), were identified. Mendelian randomisation (MR) revealed little evidence of a causal effect of mJSW on HOA (βIVW-0.01 [95% CI -0.19, 0.17]). However, MR-Clust analysis suggested the null MR estimates reflected the net effect of two distinct causal mechanisms cancelling each other out, one of which was protective, whereas the other increased HOA susceptibility. For the latter mechanism, all loci were positively associated with height, suggesting mechanisms leading to greater height and mJSW increase the risk of HOA in later life.ConclusionsGWAS and MR analyses suggested one group of mJSW loci reduces HOA risk via increased mJSW, suggesting possible utility as targets for chondroprotective therapies. The second group of mJSW loci increased HOA risk, despite increasing mJSW, but were also positively related to height, suggesting they contribute to mJSW and HOA risk via a growth-related mechanism.

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.

The importance, and the difficulty, of generating biosynthetic articular cartilage is widely recognized. Problems arise from obtaining sufficient stiffness, toughness and longevity in the material and integration of new material into existing cartilage and bone. Much work has been done on chondrocytes and tissue macromolecular components while water, which comprises the bulk of the tissue, is largely seen as a passive component; the ‘solid matrix’ is believed to be the main load-bearing element most of the time. Water is commonly seen as an inert filler whose restricted flow through the tissue is believed to be sufficient to generate the properties measured. We propose that this model should be turned on its head. Water comprises 70–80% of the matrix and has a bulk modulus considerably greater than that of cartilage. We suggest that the macromolecular components structure the water to support the loads applied. Here, we shall examine the structure and organization of the main macromolecules, collagen, aggrecan and hyaluronan, and explore how water interacts with their polyelectrolyte nature. This may inform the biosynthetic process by identifying starting points to enable developing tissue properties to guide the cells into producing the appropriate macromolecular composition and structure.

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.

Background/Aims Radiographic hip osteoarthritis (rHOA) is traditionally defined on hip x-rays, using subjective methods such as Kellgren-Lawrence scoring. Associations between subjective rHOA measures and symptoms are inconsistent. Applying digital tools to high-resolution dual-energy X-ray absorptiometry (DXA) scans, we aimed to develop a novel semi-automated classifier for rHOA and evaluate the face validity of the classifier based on relationships with hip pain, hospital diagnosed OA (HES OA), and risk of total hip replacement (THR). Methods Using hip DXAs in UK Biobank, osteophyte grades 0-3 were assigned based on manually measured osteophyte area. Minimum joint space width (mJSW) was automatically measured using outline points placed by a machine learning-based algorithm and then used to categorise individuals into joint space narrowing (JSN) grades 0-3. Osteophyte and JSN grades were combined, using a novel system giving greater to weight to osteophytes, to categorise individuals into rHOA grades 0-4. Logistic regression giving odds ratios (OR) was used to examine associations between rHOA grade and hip pain, and HES OA. Cox proportional hazard models giving hazard ratios (HR) were used to examine associations between rHOA grade and subsequent THR. Our adjusted model included age, sex, height and weight as covariates. Results 40,340 individuals were included in the study (mean age 63.7 [range 44-82], 19294/21046 male/female). 32758 (81.2%) had rHOA grade 0, 4565 (11.3%) grade 1, 2317 (5.7%) grade 2, 543 (1.3%) grade 3, 157 (0.4%) grade 4, with all features of rHOA being more common in males than females. rHOA grades ≥2 were associated with all three clinical outcomes in both unadjusted and adjusted models, a clear dose-response relationship was seen with each increase in grade showing a large rise in OR/HRs (Table 1). Grade 4 rHOA was strongly predictive of THR (HR 57.70 [95%CI 38.08-87.44]). Conclusion We successfully applied a novel semi-automated classifier to over 40,000 individuals from UKB. The validity of our classifier was supported by the strong and progressive relationships observed between rHOA and hip pain, and HES OA and risk of THR. We conclude that hip DXAs provide a promising means of defining rHOA, with potential screening applications in the clinic. Disclosure B.G. Faber: None. R. Ebsim: None. F.R. Saunders: None. M. Frysz: None. C. Lindner: None. J.S. Gregory: None. R.M. Aspden: None. N.C. Harvey: None. G. Davey Smith: None. T. Cootes: None. J.H. Tobias: None.

Background Articular cartilage is known to be a viscoelastic material, however little research has explored the impact of cartilage water content and bone density on its viscoelasticity. This study aimed to isolate subchondral bone density and hydration of articular cartilage and analyse their effects on the viscoelastic properties of articular cartilage. Methods Dynamic mechanical analysis was used to test samples at frequencies of 1, 8, 12, 29, 49, 71, and 88 Hz. Synthetic bone material with densities of 663.7 kg/m3 and 156.8 kg/m3 were used to mimic the bone mineral density (BMD). Dehydration occurred in a stepwise manner at relative humidity (RH) levels of 100%, 30%, and 1%. These relative humidity levels led to water contents of approximately 76%, 8.5%, and ≈ 0% by mass, respectively. Results Samples from eight bovine femoral heads were tested under a sinusoidal load. Storage stiffness was lower on the lower substrate density. Storage stiffness, though, increased as cartilage samples were dehydrated from a water content of 76% to 8.5%; decreasing again as the water content was further reduced. Loss stiffness was lower on a lower density substrate and decreased as the water content decreased. Conclusions In conclusions, a decrease in hydration decreases the loss stiffness, but a non-linear relationship between hydration and storage stiffness may exist. Additionally, higher BMD values led to greater storage and loss stiffnesses.

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.

The intrauterine environment is known to influence foetal development and future health. Low birthweight has been linked to smaller vertebral canals in children and decreased adulthood spine bone mineral content. Perinatal factors affecting lumbar spine curvature have not yet been considered but could be important for adult spinal health, as lumbar movement during lifting, a risk factor for backpain, is associated with lordosis. To investigate this, lumbar spine magnetic resonance images at age 10 years and perinatal and maternal data (birthweight, placental weight, gestation length, crown‐heel length, maternal age, height, weight and smoking status) from 161 children born in Aberdeen in 1988–1989 were acquired. Statistical shape modelling, using principal component analysis, quantified variations in lumbar spine shape and resulting modes of variation were assessed in combination with perinatal data using correlations and analyses of covariance, adjusted for potential confounders. Spine modes 1–3 (SM1–SM3) captured 75% of the variation in lumbar spine shape. The first and third modes described the total amount (SM1) and evenness of curvature distribution (SM3). SM2 accounted for variations in antero‐posterior vertebral diameter relative to vertebral height, increasing positive scores representing a larger relative diameter. Adjusting for gestation length and sex, SM2 positively correlated with birthweight (r = 0.25, P

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.

Objectives: Hip development is influenced by mechanical loading, but associations between prenatal loading and hip shape in later life remain unexplored. Methods: We examined associations between prenatal loading indicators (gestation length, oligohydramnios (OH) and breech) obtained from obstetric records and hip shape modes (HSMs) generated using dual-energy X-ray absorptiometry images taken at age 14- and 18-years in participants from the UK Avon Longitudinal Study of Parents and Children (ALSPAC). These associations were examined in 2453 (30 OH, 105 breech) and 2330 (27 OH, 95 breech) participants with complete data at age 14- and 18-years respectively using confounder-adjusted models. Results: At 14 years HSM2 was 0.59SD lower in OH males, and HSM5 (-0.31SD) and HSM9 (-0.32SD) were lower in OH in both sexes. At 18 years HSM1 (-0.44SD) and HSM2 (-0.71SD) were lower and HSM6 (0.61SD) and HSM8 (1.06SD) were higher in OH males, whilst HSM5 was lower in OH in both sexes. OH appeared to be associated with a wider femoral neck and head, and larger lesser/greater trochanters. Only weak associations were observed between gestation length/breech and HSMs. Conclusions: These results suggest that prenatal skeletal loading, in particular oligohydramnios, may influence adolescent joint shape with associations generally stronger in males.

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.

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.

To gain initial stability for cementless fixation the acetabular components of a total hip replacement are press-fit into the acetabulum. Uneven stiffness of the acetabular bone will result in irregular deformation of the shell which may hinder insertion of the liner or lead to premature loosening. To investigate this, we removed bone cores from the ilium, ischium and pubis within each acetabulum and from selected sites in corresponding femoral heads from four cadavers for mechanical testing in unconfined compression. From a stress-relaxation test over 300 s, the residual stress, its percentage of the initial stress and the stress half-life were calculated. Maximum modulus, yield stress and energy to yield (resilience) were calculated from a load-displacement test. Acetabular bone had a modulus about 10–20%, yield stress about 25% and resilience about 40% of the values for the femoral head. The stress half-life was typically between 2–4 s and the residual stress was about 60% of peak stress in both acetabulum and femur. Pubic bone was mechanically the poorest. These results may explain uneven deformation of press-fit acetabular shells as they are inserted. The measured half-life of stress-relaxation indicates that waiting a few minutes between insertion of the shell and the liner may allow seating of a poorly congruent liner.

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 Hip osteoarthritis (OA) commonly affects older adults and leads to high morbidity. There is no preventative treatment available and total hip replacement (THR) is offered for end stage disease. Known predictors of THR include pain and radiographic OA. Hip structure has also been shown to worsen hip OA and predict THR. A better understanding of predictors of THR can aid in triaging patients and researching preventative strategies. The purpose of this study is to describe predictors of THR in community dwelling older adults.Methods At baseline, participants had assessment of radiographicOA and cam impingement (from pelvic radiographs), shape mode scores (from dual energy X-ray absorptiometry (DXA)) and hip bone mineral density (BMD) (from 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 5.0% (40 / 802). As expected, WOMAC hip pain and hip radiographic OA both predicted risk of THR. Additionally, shape mode 2 score (decreasing acetabular coverage) (RR 1.57 per SD; 95% CI 1.01-2.46), shape mode 4 score (non-spherical femoral head) (RR 0.65/SD; 95% CI 0.44-0.97), cam impingement (α >60°) (RR 2.66/SD; 95% CI 1.38-5.13), neck of femur BMD (RR 1.85/SD, 95% CI 1.4-2.44) and bone marrow lesions (BMLs) increased risk of THR (RR 5.62/unit; 95% CI 1.1 – 28.81). There was a trend for hip effusions to increase the risk of THR (RR 1.88/SD; 95% CI 0.24 to 14.78).Conclusion In addition to hip pain and radiographic hip OA, measures of hip shape, cam impingement, 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.

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.

The endocannabinoid system is known for its regulatory effects on bone metabolism through the cannabinoid receptors, Cnr1 and Cnr2. In this study we analysed the mechanical and material properties of long bones from Cnr1(-/-) mice on a C57BL/6 background. Tibiae and femora from 5- and 12-week-old mice were subjected to three-point bending to measure bending stiffness and yield strength. Elastic modulus, density and mineral content were measured in the diaphysis. Second moment of area (MOA2), inner and outer perimeters of the cortical shaft and trabecular fractional bone volume (BV/TV) were measured using micro-CT. In Cnr1(-/-) males and females at both ages the bending stiffness was reduced due to a smaller MOA2. Bone from Cnr1(-/-) females had a greater modulus than wild-type controls, although no differences were observed in males. BV/TV of 12-week-old Cnr1(-/-) females was greater than controls, although no difference was seen at 5-weeks. On the contrary, Cnr1(-/-) males had the same BV/TV as controls at 12-weeks while they had significantly lower values at 5-weeks. This study shows that deleting Cnr1 decreases the amount of cortical bone in both males and females at 12-weeks, but increases the amount of trabecular bone only in females.

Two bottlenecks impeding the genetic analysis of complex traits in rodents are access to mapping populations able to deliver gene-level mapping resolution and the need for population-specific genotyping arrays and haplotype reference panels. Here we combine low-coverage (0.15×) sequencing with a new method to impute the ancestral haplotype space in 1,887 commercially available outbred mice. We mapped 156 unique quantitative trait loci for 92 phenotypes at a 5% false discovery rate. Gene-level mapping resolution was achieved at about one-fifth of the loci, implicating Unc13c and Pgc1a at loci for the quality of sleep, Adarb2 for home cage activity, Rtkn2 for intensity of reaction to startle, Bmp2 for wound healing, Il15 and Id2 for several T cell measures and Prkca for bone mineral content. These findings have implications for diverse areas of mammalian biology and demonstrate how genome-wide association studies can be extended via low-coverage sequencing to species with highly recombinant outbred populations.

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.

Raman microscopy is a nondestructive technique requiring minimal sample preparation that can be used to measure the chemical properties of the mineral and collagen parts of bone simultaneously. Modern Raman instruments contain the necessary components and software to acquire the standard information required in most bone studies. The spatial resolution of the technique is about a micron. As it is nondestructive and small samples can be used, it forms a useful part of a bone characterization toolbox.

The primary functions of bone are to provide support and protection-mechanical functions. The aim of this chapter is to set out some of the methods that can be used to measure these properties in cortical and cancelleous bone from large (e.g., human or bovine) and small (e.g., mouse) animals. The difference between the properties of the sample (extrinsic properties) and the properties of the material (intrinsic properties) is introduced and techniques for measuring them suggested. The addition of other tests to give a complete characterization of a bone sample is presented.

Raman microscopy is a nondestructive technique requiring minimal sample preparation that can be used to measure the chemical properties of the mineral and collagen parts of bone simultaneously. Modern Raman instruments contain the necessary components and software to acquire the standard information required in most bone studies. The spatial resolution of the technique is about a micron. As it is nondestructive and small samples can be used, it forms a useful part of a bone characterization toolbox.

We aimed to examine whether back pain across adulthood was associated with spine shape at age 60–64 years. Data were from 1405 participants in the MRC National Survey of Health and Development, a nationally representative British birth cohort. Back pain was ascertained during nurse interviews at ages 36, 43, 53 and 60–64 years. Cumulative exposure to back pain was then derived by counting the number of ages at which back pain was reported. Statistical shape modelling was used to characterise thoracolumbar spine shape using lateral dual-energy x-ray absorptiometry images which were ascertained at age 60–64 years. Linear regression models were used to test associations of spine shape modes (SM) with: (1) cumulative exposure to back pain; (2) back pain reports during different periods of adulthood. After adjusting for sex, higher cumulative exposure to back pain across adulthood was associated with wedge-shaped L4-5 disc (lower SM4 scores) and smaller disc spaces (higher SM8 scores) in both sexes. In addition, reporting of back pain at ages 53 and/or 60–64 years was associated with smaller L4-5 disc space (lower SM6 scores) in men but not women. These findings suggest that back pain across adulthood may be associated with specific variations in spine shapes in early old age.

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.

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.

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.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.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.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.

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.

The 2D shape of the lumbar spine in the sagittal plane can be determined from lordosis angles measured between the corresponding end-plates of the vertebral bodies or by using an active shape model (ASM) of the vertebral body outline. The ASM was previously shown to be a more efficient and reliable method, but its accuracy has not been assessed. The aim of this study was to determine the accuracy of an ASM for characterising lumbar spine shape and compare this to conventional measurements. Images of 25 different lumbar spine shapes were generated and measured, using both methods, by three independent observers. The accuracy of the ASM, determined from lordosis angles predicted by the model, was found to be better than conventional measurements.

Traditional voice research occurs within a phonetic context. Accordingly, pitch-related contributions are inseparable from those due to articulator input. In humming, articulator input is negligible. Using magnetic resonance imaging, we test the hypothesis that voice production is accompanied by pitch-related adjustments unrelated to articulatory or postural input.In this cross-sectional study, 10 healthy volunteers (five men, five women, aged 20-47 years, median 25 years), including singers (6 months to 10 years tuition, median 2 years) and non-singers, were assessed to establish the lowest and highest notes they could comfortably sustain while humming over 20 seconds. With head position stable, midsagittal images were acquired while volunteers hummed these predetermined low and high notes. Twenty-two craniocervical, angular, and linear dimensions defined on these images were compared using one-way repeated-measures analysis of variance. Correlations between variables were sought using Pearson correlation coefficient.We found significant differences between low- and high-note conditions in six of 22 measures and widespread pitch-related correlations between variables (r≥0.63, P0.05). Compared with low-note humming, high-note humming was accompanied by increased craniocervical angles opt/nsl and cvt/nsl (P=0.008 and 0.002, respectively); widening of the C3-menton distance (P=0.003), a rise of the larynx and hyoid in relation to the cranial base (P=0.012 and0.001, respectively), and an increased sternum-hyoid distance (P0.001).Voice production is accompanied by pitch-related adjustments that are currently being masked by, or mistakenly attributed to, articulatory or postural input, identification of which could improve understanding of mechanisms underlying speech and song.