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Raised bone density is a sporadic incidental finding on routine Dual-energy X-Ray Absorptiometry (DXA) scanning of apparently asymptomatic individuals, but may reflect an w1derlying skeletal dysplasia. I aimed to establish the prevalence of High Bone Mass(HBM) and perform the first detailed characterisation of the HBM phenotype. Methods By screening 335,115 DXA scans, 258 individuals with unexplained HBM (Ll Z-score~+3.2 plus total hip Z-score≥+1.2, or total hip Z-score≥+3.2) were recruited, from 15 UK centres. Subsequently, 236 first-degree relatives were recruited of whom 94(41 %) had HBM (Ll Z- score plus total hip Z-score≥+3.2). 61 spouses were recruited, 3 had HBM. Together unaffected relatives and spouses constituted controls. Phenotypes were established by clinical assessment, DXA, serum analyses, and forearm/ tibial peripheral quantitative computer tomography (PQCT). Cases and controls were compared using random-effects linear and logistic regression models, clustered by family, adjusted for confounders. pQCT findings were replicated using Hertfordshire Cohort Study(HCS) general population data. Results HBM affected 0.18% of DXAs. Cases had an excess of sinking when swimming (7.11 [3.65,13.84],p<0.001) (adjusted odds ratio [95% CI]), mandible enlargement (4.16 [2.34,7.39],p<0.OOl), extra bone at tendon/ligament insertions (2.07[1.13,3.78],p=0.018) and broad frame (3.55(2.12,5.95],p<0.001). Cases had larger shoe sizes (0.4[0.l,0.7]UK sizes,p=0.009, mean differences adjusted for age, gender) and increased body weight (6.2[3.5,8.9]kg,p<0.001). The latter was explained by striking increases in bone and fat mass (0.68[0.56,O.80]kg & 6.80[3.96,9.63]kg respectively, both p<0.00l). Lean mass increases. were disproportionately low. Bone resorption and formation markers were substantially reduced. HBM showed increased trabecular and cortical densities (23.7[15.5,32.0] & 28.53 [13.38,43.69]mg/ cm-, 4 & 66% tibia respectively, both p

There is strong evidence that higher bone mineral density (BMD) is a risk factor for osteoarthritis (OA), although the association with OA progression is unclear. It is uncertain if observational associations reflect a causal effect of bone on joint deterioration, or shared underlying biology. I examined the role of BMD in OA progression by determining change in radiographic sub-phenotypes (osteophytes, joint space narrowing) at the hip and knee in individuals with high bone mass (HBM, L1 and/or total hip Z-score > +3.2), comparing progression to their relatives without HBM (Chapters 6,7). HBM individuals had increased progression of radiographic OA sub-phenotypes at both joints, compared to their relatives. Metabolomics analysis did not identify any metabolic traits, and thus metabolic pathways, which could mediate the association between HBM and OA (Chapter 8). I next performed multivariable Mendelian randomization (MVMR) in UK Biobank to determine if BMD exerts a causal effect on OA, independent of confounding by body mass index (BMI) (Chapter 9). MVMR identified a BMI-independent causal effect of BMD on hip and knee OA (26% and 36% increased odds per SD increase, respectively). Subsequently, I analysed the underlying biological pathways contributing to both BMD and OA, by calculating the proportion of variance in hospital-diagnosed hip and knee OA explained by genetic variation in the Wnt signalling, TGFβ superfamily and osteoclast differentiation pathways (Chapter 10). This analysis provided evidence for a BMD-independent contribution of these pathways to OA. Further MVMR analyses identified a BMI-independent causal effect of circulating IGF-1 on risk of hospital-diagnosed hip and knee OA (49% and 22% increased odds per SD increase, respectively, Chapter 11). This work suggests a role of BMD in structural OA progression at the hip and knee, reflecting a direct role of bone in joint deterioration, as well as shared underlying pathways, such as the IGF-1 axis.

Background: Hip fracture risk varies by levels of deprivation and geography; however, it is not known whether social inequalities in hip fracture incidence have changed over time in England. Furthermore, the impact of deprivation on clinical outcomes after hip fracture is not established. I examined the effect of area-level social deprivation on hip fracture incidence and outcomes among older men and women in England. Methods: In the incidence study, hip fractures were identified using Hospital Episode Statistics (HES) (2001/02-2014/15) and Office for National Statistics (ONS) mid-year population estimates (2001-2014). The Index of Multiple Deprivation (IMD) was used to measure area-based deprivation (Q1 -least deprived; Q5 - most deprived). Age-adjusted incidence rate ratios (IRR)were calculated, stratified by gender, deprivation quintiles and region. In the outcomes study, hip fractures were identified using HES data linked to the National Hip Fracture Database (04/2011-03/2015) and ONS mortality data. Deprivation was measured using the IMD. Associations between deprivation and 30-day mortality and emergency 30-day readmission were examined, adjusted for age, gender and comorbidity. Mean length of stay (LOS) in NHS acute and rehabilitation hospitals ('superspell') and total NHS bed occupancy within 1-year post-fracture were calculated. Results: Over 14 years, 747,369 index hip fracture admissions were identified. Incidence was higher in more deprived areas, particularly among men: IRR Q5 vs. Q1 1.50 [95% CI 1.48,1.52] in men, 1.17 [1.16,1.18] in women. Age-standardised incidence increased for men across all deprivation quintiles from 2001-2014. Among women, incidence fell more amongst those least deprived compared to most deprived (year by deprivation interaction p<0.001). Age-standardised hip fracture incidence was highest in the most deprived areas in the North of England compared to the Midlands and the South for both women and men. Over 4 years, 218,907 index hip fracture admissions were identified. Greater deprivation was associated with higher 30-day mortality (adjusted OR 1.23 [1.17,1.30], p < 0.001). Among survivors, mean superspell LOS was longer in the most deprived versus least deprived quintile (Q5: 24.4 [SD 21.7] days, Q1: 23.3 [22.1], p < 0.001). Emergency 30-day readmission was higher in those most deprived compared to least deprived (adjusted OR 1.27 [1.22,1.32], p < 0.001). A similar trend was observed when assessing mean total NHS bed occupancy. Conclusions: Deprivation is a stronger relative predictor of hip fracture incidence in men than women. Absolute inequalities in hip fracture incidence are greatest in the North of England. Furthermore, increasing deprivation is associated with higher 30-day mortality and, among those who survive, greater healthcare utilisation after hip fracture. These study findings highlight the need for greater focus on addressing social inequalities in hip fracture care in England.