Comparison between UK Biobank and Shanghai Changfeng suggests distinct hip morphology may contribute to ethnic differences in the prevalence of hip osteoarthritis.

OBJECTS: Joint morphology is a risk factor for hip osteoarthritis (HOA) and could explain ethnic differences in HOA prevalence. Therefore, we aimed to compare the prevalence of radiographic HOA (rHOA) and hip morphology between the predominantly White UK Biobank (UKB) and exclusively Chinese Shanghai Changfeng (SC) cohorts. METHODS: Left hip iDXA scans were used to quantify rHOA, from a combination of osteophytes (grade ≥1) and joint space narrowing (grade ≥1), and hip morphology. Using an 85-point Statistical Shape Model (SSM) we evaluated cam (alpha angle ≥60°) and pincer (lateral centre-edge angle (LCEA) ≥45°) morphology and acetabular dysplasia (LCEA <25°). Diameter of femoral head (DFH), femoral neck width (FNW), and hip axis length (HAL) were also obtained from these points. Results were adjusted for differences in age, height, and weight and stratified by sex. RESULTS: Complete data were available for 5924 SC and 39,020 White UKB participants with mean ages of 63.4 and 63.7 years old. rHOA prevalence was considerably lower in female (2.2% versus 13.1%) and male (12.0% and 25.1%) SC compared to UKB participants. Cam morphology, rarely seen in females, was less common in SC compared with UKB males (6.3% versus 16.5%). Composite SSM modes, scaled to the same overall size, revealed SC participants to have a wider femoral head compared to UKB participants. FNW and HAL were smaller in SC compared to UKB, whereas DFH/FNW ratio was higher in SC. CONCLUSIONS: rHOA prevalence is lower in Chinese compared with White individuals. Several differences in hip shape were observed, including frequency of cam morphology, FNW, and DFH/FNW ratio. These characteristics have previously been identified as risk factors for HOA and may contribute to observed ethnic differences in HOA prevalence.

A novel semi-automated classifier of hip osteoarthritis on DXA images shows expected relationships with clinical outcomes in UK Biobank.

OBJECTIVE: Conventional scoring methods for radiographic hip OA (rHOA) are subjective and show inconsistent relationships with clinical outcomes. To provide a more objective rHOA scoring method, we aimed to develop a semi-automated classifier based on DXA images and confirm its relationships with clinical outcomes. METHODS: Hip DXAs in UK Biobank (UKB) were marked up for osteophyte area from which acetabular, superior and inferior femoral head osteophyte grades were derived. Joint space narrowing (JSN) grade was obtained automatically from minimum joint space width (mJSW) measures. Clinical outcomes related to rHOA comprised hip pain, hospital diagnosed OA (HES OA) and total hip replacement. Logistic regression and Cox proportional hazard modelling were used to examine associations between overall rHOA grade (0-4; derived from combining osteophyte and JSN grades) and the clinical outcomes. RESULTS: A toal of 40 340 individuals were included in the study (mean age 63.7), of whom 81.2% had no evidence of rHOA, while 18.8% had grade ≥1 rHOA. Grade ≥1 osteophytes at each location and JSN were associated with hip pain, HES OA and total hip replacement. Associations with all three clinical outcomes increased progressively according to rHOA grade, with grade 4 rHOA and total hip replacement showing the strongest association [57.70 (38.08-87.44)]. CONCLUSIONS: Our novel semi-automated tool provides a useful means for classifying rHOA on hip DXAs, given its strong and progressive relationships with clinical outcomes. These findings suggest DXA scanning can be used to classify rHOA in large DXA-based cohort studies supporting further research, with the future potential for population-based screening.

Analysis of hydration and subchondral bone density on the viscoelastic properties of bovine articular cartilage.

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.

Statistical shape modelling provides a responsive measure of morphological change in knee osteoarthritis over 12 months.

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.

Associations between prenatal indicators of mechanical loading and proximal femur shape: findings from a population-based study in ALSPAC offspring.

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.

Is intrinsic lumbar spine shape associated with lumbar disc degeneration? An exploratory study.

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.

Perinatal factors associate with vertebral size and shape but not lumbar lordosis in 10-year-old children.

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 < 0.01), placental weight (r = 0.20, P = 0.04), crown-heel length (r = 0.36, P < 0.001) and maternal weight (r = 0.19, P = 0.04), and negatively with maternal age (r = -0.22, P = 0.02). SM2 scores were lower in girls (P < 0.001) and in the low birthweight group (P = 0.02). There were no significant differences in SM1 and SM3 scores between birthweight groups, boys and girls or children of smokers (31%) and non-smokers (69%). In conclusion, some perinatal factors were associated with vertebral body morphology but had little effect on lumbar curvature.

Statistical shape modelling of hip and lumbar spine morphology and their relationship in the MRC National Survey of Health and Development.

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.

MRI and the distribution of bone marrow fat in hip osteoarthritis.

PURPOSE: To characterize the distribution of bone marrow fat in hip osteoarthritis (OA) using magnetic resonance imaging (MRI) and to assess its use as a potential biomarker. MATERIALS AND METHODS: In all, 67 subjects (39 female, 28 male) with either total hip replacement (THA) or different severities of radiographic OA, assessed by Kellgren-Lawrence grading (KLG), underwent 3T MRI of the pelvis using the IDEAL sequence to separate fat and water signals. Six regions of interest (ROIs) were identified within the proximal femur. Within each ROI the fractional-fat distribution, represented by pixel intensities, was described by its mean, standard deviation, skewness, kurtosis, and entropy. RESULTS: Hips were graded: 12 as severe symptomatic (THA), 33 had KLG0 or 1, 9 were KLG2, 11 with KLG3, and 2 with KLG4 were analyzed together. The fractional-fat content in the whole proximal femur did not vary with severity in males (mean (SD) 91.2 (6.0)%) but reduced with severity in females from 89.1 (6.7)% (KLG0,1), 91.5 (2.9)% (KLG2), 85.8 (16.7)% (KLG3,4) to 77.5 (11.9)% (THA) (analysis of variance [ANOVA] P = 0.029). These differences were most pronounced in the femoral head, where mean values fell with OA severity in both sexes from 97.9% (2.5%) (KLG0,1) to 73.0% (25.9%) (THA, P < 0.001) with the largest difference at the final stage. The standard deviation and the entropy of the distribution both increased (P < 0.001). CONCLUSION: Descriptors of the fractional fat distribution varied little with the severity of OA until the most severe stage, when changes appeared mainly in the femoral head, and have, therefore, limited value as biomarkers. LEVEL OF EVIDENCE: 2 J. Magn. Reson. Imaging 2017;45:42-50.

Viscoelastic properties of human and bovine articular cartilage: a comparison of frequency-dependent trends.

BACKGROUND: The purpose of this study was to compare the frequency-dependent viscoelastic properties of human and bovine cartilage. METHODS: Full-depth cartilage specimens were extracted from bovine and human femoral heads. Using dynamic mechanical analysis, the viscoelastic properties of eight bovine and six human specimens were measured over the frequency range 1 Hz to 88 Hz. Significant differences between bovine and human cartilage viscoelastic properties were assessed using a Mann-Whitney test (p < 0.05). RESULTS: Throughout the range of frequencies tested and for both species, the storage modulus was greater than the loss modulus and both were frequency-dependent. The storage and loss moduli of all human and bovine cartilage specimens presented a logarithmic relationship with respect to frequency. The mean human storage modulus ranged from 31.9 MPa to 43.3 MPa, while the mean bovine storage modulus ranged from 54.0 MPa to 80.5 MPa; bovine storage moduli were 1.7 to 1.9 times greater than the human modulus. Similarly, the loss modulus of bovine cartilage was 2.0 to 2.1 times greater than human. The mean human loss modulus ranged from 5.3 MPa to 8.5 MPa while bovine moduli ranged from 10.6 MPa to 18.1 MPa. CONCLUSION: Frequency-dependent viscoelastic trends of bovine articular cartilage were consistent with those of human articular cartilage; this includes a similar frequency dependency and high-frequency plateau. Bovine cartilage was, however, 'stiffer' than human by a factor of approximately 2. With these provisos, bovine articular cartilage may be a suitable dynamic model for human articular cartilage.

Reproducibility and Diagnostic Accuracy of Kellgren-Lawrence Grading for Osteoarthritis Using Radiographs and Dual-Energy X-ray Absorptiometry Images.

Advances in image quality from modern dual-energy X-ray absorptiometry (DXA) scanners now allow near radiograph-like quality images at a low radiation dose. This opens potential new applications for the use of DXA scanners to study other musculoskeletal conditions, such as osteoarthritis, which is often investigated by visual assessment of radiographs. Together, osteoporosis and osteoarthritis are the 2 most common musculoskeletal conditions, both of which primarily affect older people. The aim of this study was to determine whether Kellgren-Lawrence grading of DXA images can be used to grade hip osteoarthritis as effectively as radiographs. People who had attended for recent pelvic radiographs underwent DXA of hips (50 hips from 25 people) using a GE Healthcare iDXA scanner. Three observers assigned Kellgren-Lawrence grades to each image, and grading was repeated at least 1 week apart. Intraobserver and interobserver reliability for radiographs and DXA images were calculated using quadratic-weighted kappa (QWK). People were recalled 12 months later, and the tests were repeated with both the radiograph and DXA scans taken within 2 weeks of each other. Hip DXA intraobserver reproducibility achieved a QWK range of 0.88-0.95 and interobserver reproducibility of 0.85-0.88, similar to QWK from hip radiographs. Intraobserver reliability between subject-matched radiograph and iDXA images revealed QWK ranging between 0.80 and 0.88. Reproducibility of hip osteoarthritis grading using DXA was comparable with that of radiographs in this study and similar to repeatability scores previously published in literature. Given the lower radiation dose and the opportunity to simultaneously investigate osteoporosis, DXA presents an attractive imaging option for osteoarthritis.

The lumbar spine has an intrinsic shape specific to each individual that remains a characteristic throughout flexion and extension.

PURPOSE: We have previously shown that the lumbar spine has an intrinsic shape specific to the individual and characteristic of sitting, standing and supine postures. The purpose of this study was to test the hypothesis that this intrinsic shape is detectable throughout a range of postures from extension to full flexion in healthy adults. METHODS: Sagittal images of the lumbar spine were taken using a positional MRI with participants (n = 30) adopting six postures: seated extension, neutral standing, standing with 30, 45 and 60° and full flexion. Active shape modelling (ASM) was used to identify and quantify 'modes' of variation in the shape of the lumbar spine. RESULTS: ASM showed that 89.5% of the variation in the shape of the spine could be explained by the first two modes; describing the overall curvature and the distribution of curvature of the spine. Mode scores were significantly correlated between all six postures (modes 1-9, r = 0.4-0.97, P < 0.05), showing that an element of intrinsic shape was maintained when changing postures. The spine was most even in seated extension (P < 0.001) and most uneven between 35 and 45° flexion (P < 0.05). CONCLUSIONS: This study shows that an individual's intrinsic lumbar spine shape is quantifiable and detectable throughout lumbar flexion and extension. These findings will enable the role of lumbar curvature in injury and low back pain to be assessed in the clinic and in the working and recreational environments.

Associations between life course longitudinal growth and hip shapes at ages 60-64 years: evidence from the MRC National Survey of Health and Development.

OBJECTIVE: We sought to examine associations between height gain across childhood and adolescence with hip shape in individuals aged 60-64 years from the Medical Research Council National Survey of Health and Development, a nationally representative British birth cohort. METHODS: Height was measured at ages 2, 4, 6, 7, 11 and 15 years, and self-reported at age 20 years. 10 modes of variation in hip shape (HM1-10), described by statistical shape models, were previously ascertained from DXA images taken at ages 60-64 years. Associations between (1) height at each age; (2) Super-Imposition by Translation And Rotation (SITAR) growth curve variables of height size, tempo and velocity; and (3) height gain during specific periods of childhood and adolescence, and HM1-10 were tested. RESULTS: Faster growth velocity was associated with a wider, flatter femoral head and neck, as described by positive scores for HM6 (regression coefficient 0.014; 95% CI 0.08 to 0.019; p<0.001) and HM7 (regression coefficient 0.07; 95% CI 0.002 to 0.013; p=0.009), and negative scores for HM10 (regression coefficient -0.006; 95% CI -0.011 to 0.00, p=0.04) and HM2 (males only, regression coefficient -0.017; 95% CI -0.026 to -0.09; p<0.001). Similar associations were observed with greater height size and later height tempo. Examination of height gains during specific periods of childhood and adolescence identified those during the adolescence period as being most consistently associated. CONCLUSION: Our analyses suggest that individual growth patterns, particularly in the adolescent period, are associated with modest variations in hip shape at 60-64 years, which are consistent with features seen in osteoarthritis.

Dual-energy X-ray absorptiometry derived knee shape may provide a useful imaging biomarker for predicting total knee replacement: Findings from a study of 37,843 people in UK Biobank.

Objective: We aimed to create an imaging biomarker for knee shape using knee dual-energy x-ray absorptiometry (DXA) scans and investigate its potential association with subsequent total knee replacement (TKR), independently of radiographic features of knee osteoarthritis and established risk factors. Methods: Using a 129-point statistical shape model, knee shape (expressed as a B-score) and minimum joint space width (mJSW) of the medial joint compartment (binarized as above or below the first quartile) were derived. Osteophytes were manually graded in a subset of images and an overall score was assigned. Cox proportional hazards models were used to examine the associations of B-score, mJSW and osteophyte score with TKR risk, adjusting for age, sex, height and weight. Results: The analysis included 37,843 individuals (mean age 63.7 years). In adjusted models, B-score was associated with TKR: each unit increase in B-score, reflecting one standard deviation from the mean healthy shape, corresponded to a hazard ratio (HR) of 2.25 (2.08, 2.43), while a lower mJSW had a HR of 2.28 (1.88, 2.77). Among the 6719 images scored for osteophytes, mJSW was replaced by osteophyte score in the most strongly predictive model for TKR. In ROC analyses, a model combining B-score, osteophyte score, and demographics outperformed a model including demographics alone (AUC â€‹= â€‹0.87 vs 0.73). Conclusions: Using statistical shape modelling, we derived a DXA-based imaging biomarker for knee shape that was associated with kOA progression. When combined with osteophytes and demographic data, this biomarker may help identify individuals at high risk of TKR, facilitating targeted interventions.

Femoral neck width genetic risk score is a novel independent risk factor for hip fractures.

Femoral neck width (FNW) derived from DXA scans may provide a useful adjunct to hip fracture prediction. Therefore, we investigated whether FNW is related to hip fracture risk independently of femoral neck bone mineral density (FN-BMD), using a genetic approach. FNW was derived from points automatically placed on the proximal femur using hip DXA scans from 38 150 individuals (mean age 63.8 yr, 48.0% males) in UK Biobank (UKB). Genome-wide association study (GWAS) identified 71 independent genome-wide significant FNW SNPs, comprising genes involved in cartilage differentiation, hedgehog, skeletal development, in contrast to SNPs identified by FN-BMD GWAS which primarily comprised runx1/Wnt signaling genes (MAGMA gene set analyses). FNW and FN-BMD SNPs were used to generate genetic instruments for multivariable Mendelian randomization. Greater genetically determined FNW increased risk of all hip fractures (odds ratio [OR] 1.53; 95% CI, 1.29-1.82 per SD increase) and femoral neck fractures (OR 1.58;1.30-1.92), but not trochanteric or forearm fractures. In contrast, greater genetically determined FN-BMD decreased fracture risk at all 4 sites. FNW and FN-BMD SNPs were also used to generate genetic risk scores (GRSs), which were examined in relation to incident hip fracture in UKB (excluding the FNW GWAS population; n = 338 742, 3222 cases) using a Cox proportional hazards model. FNW GRS was associated with increased risk of all incident hip fractures (HR 1.08;1.05-1.12) and femoral neck fractures (hazard ratio [HR] 1.10;1.06-1.15), but not trochanteric fractures, whereas FN-BMD GRS was associated with reduced risk of all hip fracture types. We conclude that the underlying biology regulating FNW and FN-BMD differs, and that DXA-derived FNW is causally related to hip fractures independently of FN-BMD, adding information beyond FN-BMD for hip fracture prediction. Hence, FNW derived from DXA analyses or a FNW GRS may contribute clinically useful information beyond FN-BMD for hip fracture prediction.

Femoral neck width (FNW) derived from DXA scans may provide useful information about hip fracture prediction, over and above that provided by BMD measurements. Therefore, we investigated whether FNW is related to hip fracture risk independently of BMD, using a genetic approach. FNW was derived from points automatically placed on the hip in DXA scans obtained from 38 150 individuals (mean age 63.8 yr, 48.0% males) in UK Biobank. Seventy-one distinct genetic factors were found to be associated with FNW. Individuals who were predicted by their genes to have greater FNW had a higher risk of hip but not forearm fractures. In contrast, those with greater genetically determined BMD of the femoral neck had a lower risk of both hip and forearm fractures. We conclude that the underlying biology regulating FNW and BMD of the femoral neck differs, and that FNW derived from DXA analyses may contribute clinically useful information beyond BMD for hip fracture prediction.

Endothelial nitric oxide synthase is not essential for nitric oxide production by osteoblasts subjected to fluid shear stress in vitro.

Endothelial nitric oxide synthase (eNOS) has long been held responsible for NO production by mechanically stimulated osteoblasts, but this has recently been disputed. We investigated whether one of the three known NOS isoforms is essential for NO production by mechanically stimulated osteoblasts in vitro and revisited the bone phenotype of the eNOS-/- mouse. Osteoblasts, obtained as outgrowths from mouse calvaria or long bones of wild-type (WT), eNOS-/-, inducible NOS-/- (iNOS-/-), or neuronal NOS-/- (nNOS-/-) mice, were subjected to mechanical stimulation by means of pulsating fluid flow (PFF); and NO production was determined. Tibiae and femora from 8-week-old mice were subjected to µCT and three-point bending tests. Deletion of single NOS isoforms did not lead to significant upregulation of alternate isoforms in cultured osteoblasts from WT, eNOS-/-, iNOS-/-, or nNOS-/- mice. Expression of eNOS mRNA in osteoblasts was below our detection limit, and no differences in growth between WT and eNOS-/- osteoblasts were found. PFF increased NO production by approximately fourfold in WT and eNOS-/- osteoblasts and significantly stimulated NO production in iNOS-/- and nNOS-/- osteoblasts. Tibiae and femora from WT and eNOS-/- mice showed no difference in bone volume and architecture or in mechanical parameters. Our data suggest that mechanical stimuli can enhance NO production by cultured osteoblasts singly deficient for each known NOS isoform and that lack of eNOS does not significantly affect bone mass and strength at 8 weeks of age. Our data challenge the notion that eNOS is a key effector of mechanically induced bone maintenance.

A Genome-Wide Association Study Meta-Analysis of Alpha Angle Suggests Cam-Type Morphology May Be a Specific Feature of Hip Osteoarthritis in Older Adults.

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 ß = 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.

The identification of distinct protective and susceptibility mechanisms for hip osteoarthritis: findings from a genome-wide association study meta-analysis of minimum joint space width and Mendelian randomisation cluster analyses.

BACKGROUND: Hip minimum joint space width (mJSW) 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 (ii) identify which mJSW loci convey hip osteoarthritis (HOA) risk and would therefore be of therapeutic interest. METHODS: GWAS meta-analysis of hip mJSW derived from plain X-rays and DXA 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. FINDINGS: 50,745 individuals were included in the meta-analysis. 42 SNPs, which mapped to 39 loci, were identified. Mendelian randomisation (MR) revealed little evidence of a causal effect of mJSW on HOA (ORIVW 0.98 [95% CI 0.82-1.18]). 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. INTERPRETATIONS: One group of mJSW loci reduce 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 HOA risk via a growth-related mechanism. FUNDING: Primarily funded by the Medical Research Council and Wellcome Trust.

Predicting OA progression to total hip replacement: can we do better than risk factors alone using active shape modelling as an imaging biomarker?

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 Kellgren-Lawrence 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: A 1 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.

A longitudinal MRI study of muscle atrophy during lower leg immobilization following ankle fracture.

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 T(2) 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. T(2) 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.