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.

Association of Bone Shape and Alignment Analyzed Using Statistical Shape Modeling With Severity of First Metatarsophalangeal Joint Osteoarthritis.

OBJECTIVE: We aimed to explore the relationship between bone shape and radiographic severity in individuals with first metatarsophalangeal joint osteoarthritis (first MTP joint OA). METHODS: Weightbearing lateral and dorsoplantar radiographs were obtained for the symptomatic foot of 185 participants (105 females, aged 22 to 85 years) with clinically diagnosed first MTP joint OA. Participants were classified into none/mild, moderate, or severe categories using a standardized atlas. An 80-point model for lateral radiographs and 77-point model for dorsoplantar radiographs was used to define independent modes of variation using statistical shape modeling software. Odds ratios adjusted for confounders were calculated using ordinal regression to determine the association between radiographic severity and mode scores. RESULTS: After assessment and grading of radiographs, 35 participants (18.9%) were included in the none/mild first MTP joint OA severity category, 69 (37.2%) in the moderate severity category, and 81 (43.7%) in the severe category. For lateral-view radiographs, 16 modes of variation were included, which collectively represented 83.2% of total shape variance. Of these, four modes were associated with radiographic severity. For dorsoplantar-view radiographs, 15 modes of variation were included, representing 82.6% of total shape variance. Of these, six modes were associated with radiographic severity. CONCLUSIONS: Variations in the shape and alignment of the medial cuneiform, first metatarsal, and proximal and distal phalanx of the hallux are significantly associated with radiographic severity of first MTP joint OA. Prospective studies are required to determine whether bone shape characteristics are associated with the development and/or progression of this condition.

The influence of adult hip shape genetic variants on adolescent hip shape: Findings from a population-based DXA study.

OBJECTIVE: Hip shape is a well-recognized risk factor for hip osteoarthritis (OA) and hip fracture. We aimed to investigate whether the genetic variants known to be associated with adult hip shape were also associated with adolescent hip shape. METHODS: Hip DXA scans, obtained in offspring from the Avon Longitudinal Study of Parents and Children (ALSPAC) at two time points (mean ages 13.8 and 17.8 years), were used to quantify hip morphology using a 53-point Statistical Shape Model (SSM). Principal component analysis was used to generate hip shape modes (HSMs). Genetic variants which had previously shown genome-wide significant association with specific HSMs in adults were tested for association with the same HSMs in adolescents (at each timepoint separately) using SNPTEST v2. RESULTS: Complete genotypic and phenotypic data were available for 3550 and 3175 individuals at 14 and 18 years, respectively. The strongest evidence for association with adolescent hip shape was for a variant located near SOX9 (rs2158915) with consistent effects across both time points for HSM1 (age 14: beta -0.05, p = 9.9 × 10-8; age 18: -0.05, p = 3.3 × 10-6) and HSM5 (age 14: beta -0.07, p = 1.6 × 10-4; age 18: -0.1, p = 2.7 × 10-6). There was also strong evidence of association between rs10743612 (near PTHLH) and HSM1 (age 14: 0.05, p = 1.1 × 10-5; age 18: 0.04, p = 0.003) and between rs6537291 (near HHIP) and HSM2 (age 14: -0.06, p = 0.001; age 18: -0.07, p = 0.001) across both time points. The genes with the strongest associations with hip shape in adolescents, (SOX9, PTHLH and HHIP) are known to be involved in endochondral bone formation. HSM1 indicates narrower aspect ratio of the upper femur, whereas both HSM2 and HSM5 reflect variation in the femoral head size and femoral neck width, features previously found to be related to the risk of OA in later life. The SOX9 locus has previously been found to associate with increased risk of hip fracture. CONCLUSION: In conclusion, variants implicated in endochondral bone formation appear to consistently influence hip shape between adolescence and adulthood, including those aspects related to risk of hip OA and/or fracture in later life.

Anticholinergic burden in middle-aged women and recurrent falls in later life: findings from the Aberdeen prospective osteoporosis screening study (APOSS).

BACKGROUND: Anticholinergic burden (ACB) is a recognised risk factor for falls in older people; however, whether ACB in middle age predicts falls in later life is unknown. METHODS: We examined this association in the middle-aged women of the Aberdeen Prospective Osteoporosis Screening Study (APOSS). ACB was calculated at the second health visit (1997-1999, study baseline) using the Anticholinergic Cognitive Burden Scale. Outcomes were incidence of 1 fall and recurrent falls (⩾2 falls) during the 12 months prior to follow up 2007-2011. Multinomial logistic regression analyses adjusted for potential confounders including demographics, comorbidities and falls history. RESULTS: A total of 2125 women {mean age (standard deviation [SD]): 54.7 (2.2) years at baseline and 66.0 (2.2) years at follow up} were included. Prevalence of baseline ACB score of 0, 1 and ⩾2 was 87.1%, 7.3% and 5.6%, respectively. Compared with no ACB, ACB ⩾2 was associated with recurrent falls in the previous 12 months [adjusted odds ratio (OR): 2.34, 95% confidence interval (CI): 1.31, 4.19] at an average of 11 years after initial exposure. No such association was found for an ACB score of 1. CONCLUSIONS: These findings highlight the potential negative effects of anticholinergic medications in middle age. While cautious use of anticholinergic medications is advisable, further longitudinal research should be conducted to confirm these findings before any specific clinical recommendations can be made.

Describing the application of statistical shape modelling to DXA images to quantify the shape of the proximal femur at ages 14 and 18 years in the Avon Longitudinal Study of Parents and Children.

Hip shape is an important determinant of hip osteoarthritis and osteoporotic hip fracture; however, little is known about its development in childhood and adolescence. While previous studies largely focused on individual geometrical indices of hip geometry such as neck-shaft angle or femoral neck width, statistical shape modelling offers the means to quantify the entire contour of the proximal femur, including lesser trochanter and acetabular eyebrow. We describe the derivation of independent modes of variation (hip shape mode scores) to characterise variation in hip shape from dual-energy X-ray absorptiometry (DXA) images in the Avon Longitudinal Study of Parents and Children (ALSPAC) offspring, using statistical shape modelling. ALSPAC is a rich source of phenotypic and genotypic data which provides a unique opportunity to investigate the environmental and genetic influences on hip shape in adolescence, as well as comparison with adult hip shape.

Variations in Hip Shape Are Associated with Radiographic Knee Osteoarthritis: Cross-sectional and Longitudinal Analyses of the Johnston County Osteoarthritis Project.

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/m(2)). 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.