HR-pQCT measures of bone in autosomal dominant osteopetrosis highly correlate with fractures and inversely correlate with bone resorption markers.

Autosomal dominant osteopetrosis (ADO) is a rare bone disorder caused by impaired osteoclastic resorption. Despite high bone mass, ADO is paradoxically associated with increased fracture risk. High-resolution peripheral quantitative computed tomography (HR-pQCT) provides unique, low-radiation assessments of bone, but prior studies in ADO are limited to small case series. Using baseline cross-sectional data from an ongoing natural history study, we characterized HR-pQCT phenotypes in adults with ADO and explored associations with self-reported fracture history and bone turnover markers. HR-pQCT outcomes at the distal ends and shafts of the radius and tibia in 48 adults with ADO were compared to 144 matched controls (1, 3 ratio). In addition, z-scores for outcomes in ADO were calculated using established reference data. At trabecular-rich distal sites, ADO demonstrated markedly elevated total volumetric bone mineral density (vBMD), trabecular vBMD, trabecular bone volume fraction, trabecular thickness, and estimated failure load (all p<0.001), with values often approaching or exceeding twice those in controls. At cortical-rich shaft sites, total vBMD, bone area, bone area fraction, and cortical thickness were greater in ADO (all p<0.05). However, there was considerable interindividual variability, with some individuals having normal z-scores while others exhibited z-scores exceeding +20. The phenotype reflected increased bone mass rather than mineralization-cortical vBMD was normal and tissue mineral density was normal-to-lower in ADO. Outcomes at both distal and shaft sites were strongly correlated with lifetime fracture number (Spearman ρ=0.64-0.75, p<0.001), indicating ADO individuals with the "strongest" bones (via micro-finite element modeling) reported most fractures. The outcomes were correlated inversely with serum C-telopeptide and positively with serum tartrate resistant acid phosphatase 5b, consistent with ADO being rich with dysfunctional osteoclasts. Overall, the data reveal the profound, yet variable, phenotype in ADO and indicate that HR-pQCT measures correlate with disease severity and represent potential surrogate endpoints for future therapeutic trials.