SUMMARY: Ex vivo analyses of humeri and radii from an anthropological collection and in vivo analyses of the distal radius of retired men indicate that occupation-dependent loading positively influences bone strength by an increase of bone size when young followed by a slowdown of the age-related endocortical and trabecular bone alteration. INTRODUCTION: Skeleton responds to mechanical stimuli, but it is not established whether chronic loading in the context of occupational activities (OA) influences bone properties. We assessed the impact of occupation-dependent loading on upper limb bone strength. METHODS: Individuals were classified according to the intensity of physical loading associated with their OA in two models. Ex vivo, computed tomography scans of the humeri and radii of 219 male skeletons (age of death, 20-93 years) from an anthropological collection of the 20th century (Simon collection) were used to determine estimates of bone strength and cross-sectional geometry. In vivo, distal radius were analysed in 180 men enrolled in the Geneva Retirees Cohort study using high-resolution peripheral quantitative computed tomography and finite element analysis. RESULTS: Heavy-loading OA was associated with higher bone strength in both models. This benefit was associated with higher total area (Tt.Ar), medullary area (Me.Ar) and cortical area (Ct.Ar) in young adult skeletons, but the difference decreased in older age. In older men, the humerus supporting heavy loading had a lower Me.Ar. This effect resulted in greater asymmetries of the Me.Ar and the Ct.Ar/Tt.Ar ratio between the humeri of men with unilateral versus bilateral heavy-loading OA. In vivo, an additional benefit of heavy-loading OA was observed on the distal radius trabecular density and microstructure. CONCLUSION: Repeated occupation-dependent loading positively influences bone strength by an increase of bone size when young followed by a slowdown of the age-related endocortical and trabecular bone alteration. These data supports the necessity to promote bone health in the context of sedentary occupation.