External bone size identifies different strength-decline trajectories for the male human femora

Understanding skeletal aging and predicting fracture risk is increasingly important with a growing elderly population. We hypothesized that when categorized by external bone size, the male femoral diaphysis would show different strength-age trajectories which can be explained by changes in morphology, composition and collagen cross-linking. Cadaveric male femora were sorted into narrow (n = 15, 26-89 years) and wide (n = 15, 29-82 years) groups based upon total cross-sectional area of the mid-shaft normalized to bone length (Tt.Ar/Le) and tested for whole bone strength, tissue-level strength, and tissue-level post-yield strain. Morphology, cortical TMD (Ct.TMD), porosity, direct measurements of enzymatic collagen cross-links, and pentosidine were obtained. The wide group alone showed significant negative correlations with age for tissue-level strength (R² = 0.50, p = 0.002), tissue-level post-yield strain (R² = 0.75, p < 0.001) and borderline significance for whole bone strength (R² = 0.14, p = 0.108). Ct.TMD correlated with whole bone and tissue-level strength for both groups, but pentosidine normalized to enzymatic cross-links correlated negatively with all mechanical properties for the wide group only. The multivariate analysis showed that just three traits for each mechanical property explained the majority of the variance for whole bone strength (Ct.Area, Ct.TMD, Log(PEN/Mature; R² = 0.75), tissue-level strength (Age, Ct.TMD, Log(DHLNL/HLNL); R² = 0.56), and post-yield strain (Age, Log(Pyrrole), Ct.Area; R² = 0.51). Overall, this highlights how inter-individual differences in bone structure, composition, and strength change with aging and that a one-size fits all understanding of skeletal aging is insufficient.