Fiona Rosemary Saunders

Breast cancer (BC) shows greatest sexual diversity. Increased diagnosis and poorer outcomes in men highlights the need to better understand its biology. We hypothesised that cancer-associated fibroblasts (CAFs), the most abundant cell type in the tumour microenvironment, might define sex-related differences. Using phenotypically matched male and female CAFs generated from breast cancer tissues, we demonstrate distinct transcriptional programmes and functional behaviours associated with extracellular matrix remodelling, cell adhesion, migration and vascular development. Compared to CAFs generated from females BC, those from males generated denser, more complex matrices promoting stronger tumour and endothelial cell adhesion, vascular growth, but less organised capillary network formation. Findings reveal fundamental sex-related variations in CAF phenotype and biology in BC. These findings highlight the need to integrate biological sex into precision oncology to identify opportunities for sex-specific therapeutic strategies in BC.

Despite advancements in fracture prediction tools and osteoporosis management, hip fractures remain a significant consequence of bone fragility, carrying a 22% 1-yr mortality rate. Hip geometric measures (GMs) have been associated with fracture risk; however, their strong correlation hinders the identification of independent influences, leaving their relative predictive value unclear. Statistical shape modeling (SSM) provides a more holistic assessment of hip shape compared to using predetermined GMs. This study aimed to evaluate whether SSM-derived hip shape from DXA scans can predict hip fracture, independently of individual GMs. Previously, we applied SSM to left hip DXA images in UK Biobank—a large prospective cohort with linked hospital records—generating 10 orthogonal hip shape modes (HSMs) that explained 86% of shape variance. Additionally, FN width (FNW), femoral head diameter (FHD), and hip axis length (HAL) were derived from these DXAs. In the current analysis, Cox proportional hazard models, adjusted for age, sex, height, weight, BMD, and GMs (FNW, HAL, and FHD), were used to examine the longitudinal associations between each HSM and first incident hospital diagnosed hip fracture. A Bonferroni adjusted p-value threshold (p < .004) was used to account for the 13 exposures. Among the 38 123 participants (mean age 63.7 yr; 52% female; mean follow-up 5 yr), 133 (0.35%) experienced subsequent hip fracture. HSM2, characterized by a narrower FNW, a higher neck shaft angle, and reduced acetabular coverage, showed a strong association with hip fracture risk (HR: 1.32, 95% CI: 1.11-1.58, p: 1.47 × 10−3), which persisted after full adjustment (1.30, 1.09-1.55, 3.27 × 10−3). There was no evidence for an association with other HSMs. These findings suggest that DXA-derived hip shape is associated with hip fracture risk independently of BMD and GMs. Incorporating global hip shape into fracture risk assessment tools could enhance prediction accuracy and inform targeted interventions.

Objectives: To estimate the prevalence of silent vertebral compression fractures (VCF) in an asymptomatic population and to assess the demographic and clinical predictors using data from the UK Biobank. Design: A cross-sectional study using artificial intelligence-assisted six-point morphometry of dual-energy x-ray absorptiometry spine images. Setting: UK Biobank imaging study at Stockport clinical research facility. Participants: 2,446 asymptomatic volunteers aged 40 to 79 years with no history of spinal trauma or vertebral fracture. Main outcome measures: VCFs were defined as greater than or equal to 20 percent height loss, measured by artificial intelligence, with manual correction of annotations and confirmation by a musculoskeletal radiologist. Association with age, sex, bone mineral density, body mass index, and back pain were analyzed. Results: Of 2,446 participants, 763 (31.1 percent) had at least one vertebra with greater than 20 percent height loss. Fracture prevalence increased with age: 26.8 percent (37 of 138) in those aged 40-49 years, 26.1 percent (196 of 752) at 50-59 years, 33.0 percent (380 of 1,153) at 60-69 years, and 37.2 percent (150 of 403) at 70-79 years. Excluding mild deformities, 18 percent of those aged 40-49 years had moderate or severe fractures (greater than 25 percent height loss). Fractures were 11.5 percent more common in men than in women. Age was a significant predictor, but bone mineral density (BMD) and body mass index (BMI) were not. Predictive models showed limited performance (sensitivity 44.4 percent, specificity 68.2 percent). Interobserver agreement was substantial (Fleiss kappa = 0.74). Conclusions: Silent VCFs are frequent by midlife, including among younger adults with normal bone density. Men are affected more often than women, and conventional risk factors inadequately identify those at risk. Earlier detection through opportunistic or population imaging may enable timely intervention and inform future screening and fracture-prevention strategies.

Normal function of the hand and, in particular, the finger joints is fundamental to the activities of daily life. Deterioration of hand and finger function can be detrimental and lead to poor quality of life. There are multiple causes of hand and finger dysfunction that can lead to pain and disability. In this review, we will consider the role of collagen and its organization within the finger joint capsules and adjacent entheses, particularly in the proximal interphalangeal joints, and aim to address three questions: (1) What are the main collagen orientations in the interphalangeal joint capsules of the human hand? (2) Is there a relationship between collagen orientation and joint function? (3) How could altering the orientation of collagen fibers affect the functional performance of the joint following injury or surgical intervention? To answer these questions, we will consider the evidence for the main collagen orientations in the finger joint capsules and entheses and investigate the relationships between structure and function. We will then consider how collagen organization is disrupted following injury and what may be potential modulators. This will provide a better understanding of how common surgical interventions affect collagen orientation in the joint capsules and highlight some implications for post‐surgical outcomes.

Hip shape is thought to be an important causal risk factor for hip osteoarthritis and fracture. We aimed to identify genetic determinants of hip shape and use these to assess causal relationships with hip osteoarthritis. Statistical hip shape modelling was used to derive 10 hip shape modes (HSMs) from DXA images in UK Biobank and Shanghai Changfeng cohorts (n_total = 43 485). Genome-wide association study meta-analyses were conducted for each HSM. Two-sample Mendelian randomisation (MR) was used to estimate causal effects between HSM and hip osteoarthritis using hip fracture as a positive control. Analysis of the first 10 HSMs identified 203 independent association signals (P < 5 × 10⁻⁹). Hip shape SNPs were also associated (P < 2.5 × 10⁻⁴) with hip osteoarthritis (n = 26) and hip fracture (n = 4). Fine mapping implicated SMAD3 and PLEC as candidate genes that may be involved in the development of hip shape and hip osteoarthritis. MR analyses suggested there was no causal effect between any HSM and hip osteoarthritis, however there was evidence that HSM2 (more obtuse neck-shaft angle) and HSM4 (wider femoral neck) have a causal effect on hip fracture (OR_IVW method 1.27 [95% CI 1.12–1.44], P = 1.79 × 10⁻⁴ and OR_IVW 0.74 [0.65–0.84], P = 7.60 × 10⁻⁶ respectively). We report the largest hip shape GWAS meta-analysis that identifies hundreds of novel loci, some of which are also associated with hip osteoarthritis and hip fracture. MR analyses suggest hip shape may not cause hip osteoarthritis but is implicated in hip fractures. Consequently, interventions targeting hip shape in older adults to prevent hip osteoarthritis may prove ineffective.

Objectives DXA scans may offer a novel means of evaluating radiographic knee osteoarthritis (rKOA) in large population studies and through opportunistic screening. We aimed to develop and apply a semi-automated method for assessing rKOA using ∼20,000 knee DXA images from UK Biobank (UKB) and assess its face validity by checking for expected relationships with clinical outcomes. Methods Right knee DXA scans were manually annotated for osteophytes to derive corresponding grades. Joint space narrowing (JSN) grades in the medial joint compartment were determined from automatically measured minimum joint space width. Overall rKOA grade (0-4) was determined by combining osteophyte and JSN grades. Logistic regression was employed to investigate the associations of osteophyte, JSN, and rKOA grades with knee pain and hospital-diagnosed knee osteoarthritis (HES-KOA). Cox proportional hazards modelling was used to examine the associations of these variables with risk of subsequent total knee replacement (TKR). Results Of the 19,595 participants included (mean age: 63.7), 19.5% had rKOA grade ≥1 (26.1% female; 12.5% male). Grade ≥1 osteophytes and grade ≥1 JSN were associated with knee pain, HES-KOA, and TKR. Higher rKOA grades were linked to stronger associations with these clinical outcomes, with the most pronounced effects observed for TKR. HRs for the association of rKOA grades with TKR were 3.28, 8.75, and 28.63 for grades 1, 2 and 3-4, respectively. Conclusions Our DXA-derived measure of rKOA demonstrated a progressive relationship with clinical outcomes. These findings support the use of DXA for classifying rKOA in large epidemiological studies and in future population-based screening. Key messages Radiographic knee osteoarthritis (rKOA) can be semi-automatically derived from DXA images. DXA-derived rKOA shows expected relationships with clinical outcomes of knee osteoarthritis. DXA imaging presents a viable method for classifying rKOA in large-scale epidemiological research.

Background: Lateral lumbar spine statistical shape models (SSM) have been used previously to describe associations with osteoarthritis and back pain. However, associations with factors such as osteoporosis, menopause and parity have not been explored.Methods and Results: A 143-point SSM, describing L1 to the top of L5, was applied to lateral spine iDXA scans from UK Biobank. Associations with self-reported osteoporosis, menopause, parity and back pain and the first 10 modes of variation were examined using adjusted binary logistic regression or linear regression (adjusted for age, height, weight and total spine BMD). We report odds ratios with 95% confidence intervals for each standard deviation change in mode.Complete data were available for 2494 women. Mean age was 61.5 (± 7.4) years. 1369 women reported going through menopause, 96 women self-reported osteoporosis and 339 women reported chronic back pain. 80% of women reported at least 1 live birth.Lumbar spine shape was not associated with back pain in this cohort. Two modes were associated with menopause (modes 1 & 2), 1 mode with parity (mode 1) and 2 modes with osteoporosis (modes 3 & 5). Mode 1 (43.6% total variation), describing lumbar curvature was positively associated with both menopause [OR 1.15 95% CI 1.00–1.33, p=0.05] and parity [OR 1.058 95% CI 1.03–1.0, p=0.01]. Mode 3, describing decreased vertebral height was positively associated with osteoporosis [OR 1.40 95% CI 1.14–1.73, p=0.001].Conclusion: Menopause and parity were associated with a curvier lumbar spine and osteoporosis with decreased vertebral height. Shape was not associated with back pain.No conflicts of interest: Sources of funding: Wellcome Trust collaborative award ref 209233