Hip Shape as a Predictor of Osteoarthritis Progression in a Prospective Population Cohort

Ahedi, H.; Aspden, Richard M.; Blizzard, Leigh; Saunders, Fiona; Cicuttini, Flavia Maria; Aitken, Dawn; Jones, Graeme; Gregory, Jennifer S.

doi:10.1002/acr.23166

Cited by 36 publications

(64 citation statements)

References 30 publications

(63 reference statements)

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“…This is both a strength and a weakness of the method. Its strength is that it can detect and isolate coordinated changes so that certain modes become indicative of pathology and can be used as imaging biomarkers . The weakness, demonstrated here, is that the overall difference in shapes between early and late walkers, using all the modes in combination, is subtle, as indicated by the superimposed shapes in Fig .…”

Section: Discussionsupporting

confidence: 88%

Age at Onset of Walking in Infancy Is Associated With Hip Shape in Early Old Age

Ireland

Saunders

Muthuri

et al. 2018

Journal of Bone and Mineral Research

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Bones’ shapes and structures adapt to the muscle and reaction forces they experience during everyday movements. Onset of independent walking, at approximately 12 months, represents the first postnatal exposure of the lower limbs to the large forces associated with bipedal movements; accordingly, earlier walking is associated with greater bone strength. However, associations between early life loading and joint shape have not been explored. We therefore examined associations between walking age and hip shape at age 60 to 64 years in 1423 individuals (740 women) from the MRC National Survey of Health and Development, a nationally representative British birth cohort. Walking age in months was obtained from maternal interview at age 2 years. Ten modes of variation in hip shape (HM1 to HM10), described by statistical shape models, were ascertained from DXA images. In sex‐adjusted analyses, earlier walking age was associated with higher HM1 and HM7 scores; these associations were maintained after further adjustment for height, body composition, and socioeconomic position. Earlier walking was also associated with lower HM2 scores in women only, and lower HM4 scores in men only. Taken together, this suggests that earlier walkers have proportionately larger (HM4) and flatter (HM1, HM4) femoral heads, wider (HM1, HM4, HM7) and flatter (HM1, HM7) femoral necks, a smaller neck‐shaft angle (HM1, HM4), anteversion (HM2, HM7), and early development of osteophytes (HM1). These results suggest that age at onset of walking in infancy is associated with variations in hip shape in older age. Early walkers have a larger femoral head and neck and smaller neck‐shaft angle; these features are associated with reduced hip fracture risk, but also represent an osteoarthritic‐like phenotype. Unlike results of previous studies of walking age and bone mass, associations in this study were not affected by adjustment for lean mass, suggesting that associations may relate directly to skeletal loading in early life when joint shape changes rapidly. © 2018 American Society for Bone and Mineral Research.

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Section: Discussionsupporting

confidence: 88%

Age at Onset of Walking in Infancy Is Associated With Hip Shape in Early Old Age

Ireland

Saunders

Muthuri

et al. 2018

Journal of Bone and Mineral Research

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“…Although this represents the first reported GWAS for hip shape, previous candidate gene studies (7,8) have examined associations between OA susceptibility loci and hip shape, following application of SSM to radiographs (Supplemental Transcription factor primarily involved in chondrogenesis, (42) SOX9 activity can be increased through being targeted by PTHLH (33) Campomelic dysplasia, (43) Pierre Robin sequence, (44) Cooks syndrome (45) Chondrodysplasia and abnormal joint formation (46) GSC (14q32.13, rs1243579: upstream)…”

Section: Discussionmentioning

confidence: 99%

“…(16) This implied relationship between hip shape and hip OA is in-keeping with reported associations between hip DXA-derived hip shape, obtained using the same SSM method as used here, and hip OA. (8,9) For example, a wider upper femur as reflected by HSM1, associated with 12p11.22 and 21q22.12 loci related to hip OA, might alter biomechanical forces of the hip and hence risk of hip OA. Femoral head size and shape, related to HSM2 (Supplemental Fig.…”

Section: Astn2mentioning

confidence: 99%

“…SSM has recently been applied to DXA scans to explore the role of hip shape in the incidence and progression of hip OA, using a similar approach to radiograph-based analyses described above, with the exception that shape models also included the acetabular roof. (8,9) In the present study, we performed the first GWAS meta-analysis to identify novel genetic factors associated with hip shape, based on measures derived from hip DXA scans by SSM, after combining scans from five distinct population-based cohorts to ensure a sufficiently large sample (n ¼ 15,934) for genetic discovery.…”

Section: Introductionmentioning

confidence: 99%

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Identification of Novel Loci Associated With Hip Shape: A Meta-Analysis of Genomewide Association Studies

Baird

Evans

Kamanu

et al. 2018

Journal of Bone and Mineral Research

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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.

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“…In this study, we investigated the influence that Gdf5 and its broad regulatory domains have on hip morphology, in the context of shape parameters relevant to OA, DDH, and dislocation. We revealed that: (1) Gdf5 loss results in substantial dysmorphologies to the proximal femur and acetabulum in line with known features involved in hip instability, developmental dislocation, injury, and adult onset OA; (2) Compared to upstream regulatory sequences, downstream regulatory sequences of Gdf5/GDF5 drive stronger, more ubiquitous prenatal hip expression and uniquely control postnatal hip expression; (3) This regulatory structure is functionally important as downstream sequences were capable of restoring Gdf5 loss-of-function phenotypes to normal, a situation not observed when using the upstream region. These latter two findings have important ramifications to how we understand GDF5 and its association with OA and hip dysplasia/dislocation.…”

Section: Discussionmentioning

confidence: 95%

The Role of Gdf5 Regulatory Regions on Development of Hip Morphology and Susceptibility to Osteoarthritis and Dislocation

Capellini

Kiapour

Cao

et al. 2018

Preprint

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Given GDF5 involvement in hip development, and osteoarthritis (OA) and developmental hip dysplasia (DDH) risk, here we sought to assess the role(s) of GDF5 and its regulatory sequence on the development of hip morphology linked to injury risk. The brachypodism (bp) mouse, which harbors a Gdf5 inactivating mutation, was used to survey how Gdf5 loss of function impacts the development of hip morphology. Two transgenic Gdf5 reporter BAC lines were used to assess the spatiotemporal expression of Gdf5 regulatory sequences. Each BAC line was also used to assess the functional roles of upstream and downstream sequence on hip morphology. bp/bp mice had shorter femora with smaller femoral heads and necks as well as larger alpha angles, smaller anterior offsets, and smaller acetabula, compared to bp/+ mice (p<0.04). Regulatory sequences downstream of Gdf5 drove strong prenatal (E17) expression and low postnatal (6 months) expression across regions of femoral head and acetabulum. Conversely, upstream regulatory sequences drove very low expression at E17 and no detectable expression at 6 months. Importantly, downstream, but not upstream Gdf5 regulatory sequences fully restored all the key morphologic features disrupted in bp/bp mice. Hip morphology is profoundly affected by Gdf5 absence, and downstream regulatory sequences mediate its effects by controlling Gdf5 expression during development. This downstream region contains numerous enhancers harboring risk variants related to hip OA, DDH, and dislocation. We posit that subtle alterations to morphology driven by changes in downstream regulatory sequence underlie this locus’ role in hip injury risk.

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Hip Shape as a Predictor of Osteoarthritis Progression in a Prospective Population Cohort

Abstract: 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.

Cited by 36 publications

References 30 publications

Age at Onset of Walking in Infancy Is Associated With Hip Shape in Early Old Age

Age at Onset of Walking in Infancy Is Associated With Hip Shape in Early Old Age

Identification of Novel Loci Associated With Hip Shape: A Meta-Analysis of Genomewide Association Studies

The Role of Gdf5 Regulatory Regions on Development of Hip Morphology and Susceptibility to Osteoarthritis and Dislocation

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