The epidemiology of high bone mass

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<O.OOl), reduced endosteal expansion and marrow cavity size. Whilst muscle volumes were similar, subcutaneous and intramuscular fat was increased. Key findings replicated using HCS controls. Conclusion Findings support a skeletal dysplasia, increased cortical density and reduced bone turnover, with a potential metabolic phenotype, and suggest many HBM cases may harbour an underlying, yet undetermined, genetic disorder affecting bone mass.