Hip geometric parameters are associated with radiographic and clinical hip osteoarthritis: Findings from a cross-sectional study in UK Biobank.

OBJECTIVE: To examine the extent to which geometric parameters derived from dual-energy x-ray absorptiometry (DXA) scans in the UK Biobank study are related to hip osteoarthritis (HOA) independently of sex, age and body size. DESIGN: Femoral neck width (FNW), diameter of the femoral head (DFH) and hip axis length (HAL) were derived automatically from left hip DXA scans in UK Biobank using outline points placed around the hip by a machine-learning program. Correlations were calculated between geometric parameters, age, height, and weight. Logistic regression was used to examine the relationship of geometric parameters with radiographic HOA, hospital diagnosed HOA (HESOA), and Cox proportional hazards model to evaluate the relationship with total hip replacement (THR). Analyses were adjusted for sex, age, height, weight, and geometric parameters. RESULTS: The study consisted of 40,312 participants. In age and sex-adjusted analyses, FNW, HAL and DFH were related to increased risk of radiographic HOA. In a model adjusted for age, sex, height, weight and other geometric parameters, both FNW and HAL retained independent relationships with radiographic HOA [FNW: odds ratios 2.38 (2.18-2.59), HAL: 1.25 (1.15-1.36)], while DFH was now protective [0.55 (0.50-0.61)]. Only FNW was independently related to HESOA [2.20 (1.80-2.68)] and THR [hazard ratios 2.51 (1.89-3.32)]. CONCLUSION: Greater FNW and HAL were independently related to an increased risk of radiographic HOA, whereas greater DFH appeared to be protective. Greater FNW was independently associated with HESOA and THR. These results suggest that DXA-derived geometric parameters, particularly FNW, could help determine HOA and THR risk.

Cam morphology but neither acetabular dysplasia nor pincer morphology is associated with osteophytosis throughout the hip: findings from a cross-sectional study in UK Biobank.

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. DESIGN: Participants 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. RESULTS: 6,807 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. CONCLUSIONS: Cam 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.

Predictors of total hip replacement in community based older adults: a cohort study.

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/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.

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

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

Osteoarthritis as an organ disease: from the cradle to the grave.

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.

Significant morphological change in osteoarthritic hips identified over 6-12 months using statistical shape modelling.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Sex Differences in the Associations between L-Arginine Pathway Metabolites, Skeletal Muscle Mass and Function, and their Responses to Resistance Exercise, in Old Age.

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<0.001) were both positively associated with changes in MCSA, and ornithine was negatively associated with changes in MQ (P=0.039). CONCLUSION: Therefore, barring citrulline, there are significant sex differences in the associations between L-arginine metabolites and muscle mass and function in healthy older adults. These metabolites might enhance sarcopenia risk stratification, and the success of exercise programs, in old age.

DXA-derived hip shape is related to osteoarthritis: findings from in the MrOS cohort.

OBJECTIVE: Statistical shape modelling (SSM) of radiographs has been used to explore relationships between altered joint shape and hip osteoarthritis (OA). We aimed to apply SSM to Dual-energy X-ray Absorptiometry (DXA) hip scans, and examine associations between resultant hip shape modes (HSMs), radiographic hip OA (RHOA), and hip pain, in a large population based cohort. METHOD: SSM was performed on baseline hip DXA scans from the Osteoporotic Fractures in Men (MrOS) Study. Associations between the top ten HSMs, and prevalent RHOA from pelvic radiographs obtained 4.6 years later, were analysed in 4100 participants. RHOA was defined as Croft score ≥2. Hip pain was based on pain on walking, hip pain on examination, and Western Ontario and McMaster Universities Arthritis Index (WOMAC). RESULTS: The five HSMs associated with RHOA showed features of either pincer- or cam-type deformities. HSM 1 (increased pincer-type deformity) was positively associated with RHOA [1.23 (1.09, 1.39)] [odds ratio (OR) and 95% CI]. HSM 8 (reduced pincer-type deformity) was inversely associated with RHOA [0.79 (0.70, 0.89)]. HSM 10 (increased cam-type deformity) was positively associated with RHOA [1.21 (1.07, 1.37)]. HSM 3 and HSM 4 (reduced cam-type deformity) were inversely associated with RHOA [0.73 (0.65, 0.83) and 0.82 (0.73, 0.93), respectively]. HSM 3 was inversely related to pain on examination [0.84 (0.76, 0.92)] and walking [0.88, (0.81, 0.95)], and to WOMAC score [0.87 (0.80, 0.93)]. CONCLUSIONS: DXA-derived measures of hip shape are associated with RHOA, and to a lesser extent hip pain, possibly reflecting their role in the pathogenesis of hip OA.

The influence of the strength of bone on the deformation of acetabular shells: a laboratory experiment in cadavers.

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.

The mechanical and material properties of elderly human articular cartilage subject to impact and slow loading.

The mechanical properties of articular cartilage vary enormously with loading rate, and how these properties derive from the composition and structure of the tissue is still unclear. This study investigates the mechanical properties of human articular cartilage at rapid rates of loading, compares these with measurements at slow rates of loading and explores how they relate to the gross composition of the tissue. Full-depth femoral head cartilage biopsies were subjected to a slow, unconfined compression test followed by an impact at an energy of 78.5mJ and velocity 1.25ms(-1). The modulus was calculated from the slope of the loading curve and the coefficient of restitution from the areas under the loading and unloading curves. Tissue composition was measured as water, collagen and glycosaminoglycan contents. The maximum dynamic modulus ranged from 25 to 150MPa. These values compared with 1-3MPa measured during quasi-static loading. The coefficient of restitution was 0.502 (0.066) (mean (standard deviation)) and showed no site variation. Water loss was not detectable. Composition was not strongly associated with modulus; water and collagen contents together predicted about 25% of the variance in modulus.

How many different types of femora are there in primary hip osteoarthritis? An active shape modeling study.

We assessed the variation in proximal femoral canal shape and its association with geometric and demographic parameters in primary hip OA. In a retrospective cohort study, the joint geometry of the proximal femur was evaluated on radiographs and corresponding CT scans of 345 consecutive patients with end-stage hip OA. Active shape modeling (ASM) was performed to assess the variation in endosteal shape of the proximal femur. To identify natural groupings of patients, hierarchical cluster analysis of the shape modes was used. ASM identified 10 independent shape modes accounting for >96% of the variation in proximal femoral canal shape within the dataset. Cluster analysis revealed 10 specific shape clusters. Significant differences in geometric and demographic parameters between the clusters were observed. ASM and subsequent cluster analysis have the potential to identify specific morphological patterns of the proximal femur despite the variability in proximal femoral anatomy. The study identified patterns of proximal femoral canal shape in hip OA that allow a comprehensive classification of variation in shape and its association with joint geometry. Our data may improve future stem designs that will optimize stem fit and simultaneously allow individual restoration of hip biomechanics.

Can we improve the prediction of hip fracture by assessing bone structure using shape and appearance modelling?

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.

Analysis of sequential cytokine release after ACL reconstruction.

PURPOSE: 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. METHODS: 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. RESULTS: 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-ß suggestive of an anabolic response were found. CONCLUSION: These data support the contention that an anabolic response starts earlier than previously thought within the surgically reconstructed knee.

Non-immortalized human tenocyte cultures as a vehicle for understanding cellular aspects to tendinopathy.

The biochemical mechanisms underlying tendinopathy are obscure. We briefly describe preliminary observations of human tenocyte behaviour in culture as a vehicle for determining the role of reactive oxygen in tendon pathology.

Osteoarthritis: a problem of growth not decay?

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.

The biophysical effects of a single impact load on human and bovine articular cartilage.

Impact injury to a joint is a known risk factor for the subsequent development of secondary osteoarthritis. An in vitro model, employing a drop-tower loading machine, was used to examine the effect of an impact load on isolated articular cartilage explants from human and bovine femoral heads. Two different types of impact experiment were performed. In the first, 4 mm diameter explants were loaded using a plane-ended impactor. In the second, a modified impactor was developed that had a central 4 mm diameter plane-ended indentor which was used to load the centre of 8 mm diameter explants. This enabled the unloaded outer ring of each explant to be compared with the loaded central core. The modulus values measured using the impactor were found to be higher, compared with the indentor in both species. Scanning electron microscopy showed that cartilage surrounding the loaded central region of the 8 mm explants protected the indented tissue, and these explants showed less damage than the 4 mm samples that were fully impacted. In addition, human cartilage was found to be less damaged than bovine, possibly as a consequence of the different structure as well as of a greater thickness. Both the source of the tissue and the nature of the impact affected the type of damage observed.

Phenotypic drift in human tenocyte culture.

Tendon ruptures are increasingly common, repair can be difficult, and healing is poorly understood. Tissue engineering approaches often require expansion of cell numbers to populate a construct, and maintenance of cell phenotype is essential for tissue regeneration. Here, we characterize the phenotype of human Achilles tenocytes and assess how this is affected by passaging. Tenocytes, isolated from tendon samples from 6 patients receiving surgery for rupture of the Achilles tendon, were passaged 8 times. Proliferation rates and cell morphology were recorded at passages 1, 4, and 8. Total collagen, the ratio of collagen types I and III, and decorin were used as indicators of matrix formation, and expression of the integrin beta1 subunit as a marker of cell-matrix interactions. With increasing passage number, cells became more rounded, were more widely spaced at confluence, and confluent cell density declined from 18,700/cm2 to 16,100/cm2 ( p = 0.009). No change to total cell layer collagen was observed but the ratio of type III to type I collagen increased from 0.60 at passage 1 to 0.89 at passage 8 ( p < 0.001). Decorin expression significantly decreased with passage number, from 22.9 +/- 3.1 ng/ng of DNA at passage 1, to 9.1 +/- 1.8 ng/ng of DNA at passage 8 ( p < 0.001). Integrin expression did not change. We conclude that the phenotype of tenocytes in culture rapidly drifts with progressive passage.