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

SummaryObjectiveStatistical 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.MethodSSM 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).ResultsThe 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)].ConclusionsDXA-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.

Objective Conventional scoring methods for radiographic hip osteoarthritis (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 dual-energy X-ray absorptiometry (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 (THR). 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 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 THR. Associations with all three clinical outcomes increased progressively according to rHOA grade, with grade 4 rHOA and THR 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.

Hip OA susceptibility loci were associated with shape in this study, suggesting that these loci (and potentially yet-to-be-identified hip OA loci) could contribute to hip OA in later life via perturbing biologic pathways that mediate morphology development.

The contribution of shape changes to hip osteoarthritis (HOA) remains unclear, as is the extent to which these vary according to HOA severity. In the present study, we used statistical shape modeling (SSM) to evaluate relationships between hip shape and HOA of different severities using UK Biobank DXA images. We performed a cross-sectional study in individuals with left hip dual-energy X-ray absorptiometry (DXA) scans. Statistical shape modeling (SSM) was used to quantify hip shape. Radiographic HOA (rHOA) was classified using osteophyte size and number and joint space narrowing. HOA outcomes ranged in severity from moderate (grade 2) to severe (grade ≥3) rHOA, hospital-diagnosed HOA, and subsequent total hip replacement (THR). Confounder-adjusted logistic regression between the top 10 hip shape modes (HSMs) and OA outcomes was performed. Further models adjusted for alpha angle (AA) and lateral center-edge angle (LCEA), reflecting acetabular dysplasia and cam morphology, respectively. Composite HSM figures were produced combining HSMs associated with separate OA outcomes. A total of 40,311 individuals were included (mean 63.7 years, 47.8% male), of whom 5.7% had grade 2 rHOA, 1.7% grade ≥3 rHOA, 1.3% hospital-diagnosed HOA, and 0.6% underwent THR. Composite HSM figures for grade 2 rHOA revealed femoral neck widening, increased acetabular coverage, and enlarged lesser and greater trochanters. In contrast, grade ≥3 rHOA, hospital-diagnosed HOA, and THR were suggestive of cam morphology and reduced acetabular coverage. Associations between HSMs depicting cam morphology and reduced acetabular coverage and more severe HOA were attenuated by AA and LCEA adjustment, respectively. Relationships between hip shape and HOA differed according to severity. Notably, cam morphology and acetabular dysplasia were features of severe HOA, but unrelated to moderate disease, suggesting possible prognostic utility.

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 2.41e4.25)], JSN [1.53 (1.24e1.88)], and acetabular [1.87 (1.48 e2.36)], superior [1.94 (1.45e2.57)] and inferior [4.75 (3.44e6.57)] femoral osteophytes, and hip pain [1.48 (1.05e2.09)]. 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.

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.

To review recent findings concerning the observational relationship between hip shape and hip osteoarthritis (HOA) and their shared genetic influences, and the potential for clinical application. Recent findingsRecent observational studies have strengthened the evidence that specific shape deformities, such as cam and acetabular dysplasia, are related to HOA. Statistical shape modelling has emerged as a method to measure hip shape holistically, with the added advantage that this can be applied to DXA scan images. This has led to several additional aspects of hip shape variation being identified, such as a wider femoral neck and larger lesser trochanter, in association with HOA. Furthermore, this method has formed the basis of genetic studies identifying novel genetic influences on hip shape, several of which are shared with known genetic risk factors for HOA. SummaryShared genetic influences of hip shape and HOA raise the possibility that hip shape plays a casual role in the development of HOA, justifying preventative approaches aiming to combat these adverse consequences.