People with diabetes have increased risk of fracture disproportionate to BMD, suggesting reduced material strength (quality). We quantified the skeletal effects of type 1 diabetes in the rat. Fischer 344 and Sprague-Dawley rats (12 wk of age) were injected with either vehicle (Control) or streptozotocin (Diabetic). Forelimbs were scanned at 0, 4, 8, and 12 wk using pQCT. Rats were killed after 12 wk. We observed progressive osteopenia in diabetic rats. Trabecular osteopenia was caused by bone loss: volumetric BMD decreased progressively with time in diabetic rats but was constant in controls. Cortical osteopenia was caused by premature arrest of cortical expansion: cortical area did not increase after 4–8 wk in diabetic rats but continued to increase in controls. Postmortem μCT showed a 60% reduction in proximal tibial trabecular BV/TV in diabetic versus control rats, whereas moments of inertia of the ulnar and femoral diaphysis were reduced ∼30%. Monotonic bending tests indicated that ulna and femora from diabetic animals were ∼25% less stiff and strong versus controls. Estimates of material properties indicated no changes in elastic modulus or ultimate stress but modest (∼10%) declines in yield stress for diabetic bone. These changes were associated with a ∼50% increase in the nonenzymatic collagen cross-link pentosidine. Last, cyclic testing showed diminished fatigue life in diabetic bones at the structural (force) level but not at the material (stress) level. In summary, type 1 diabetes, left untreated, causes trabecular bone loss and a reduction in diaphyseal growth. Diabetic bone has greatly increased nonenzymatic collagen cross-links but only modestly reduced material properties. The loss of whole bone strength under both monotonic and fatigue loading is attributed mainly to reduced bone size.

The risk of bone fracture depends in part on tissue quality, not just the size and mass. This study assessed the postyield energy dissipation of cortical bone in tension as a function of age and composition. Specimens were prepared from tibiae of human cadavers in which male and female donors were divided into two age groups: middle aged (51 to 56 years, n = 9) and elderly (72 to 90 years, n = 8). By loading, unloading, and reloading a specimen with rest periods inserted in between, tensile properties at incremental strain levels were assessed. In addition, postyield toughness was estimated and partitioned as plastic strain energy related to permanent deformation, released elastic strain energy related to stiffness loss, and hysteresis energy related to viscous behavior. Porosity, mineral and collagen content, and collagen crosslinks of each specimen were also measured to determine the micro‐ and ultrastructural properties of the tissue. Age affected all the energy terms plus strength but not elastic stiffness. The postyield energy terms were correlated with porosity, pentosidine (a marker of nonenzymatic crosslinks), and collagen content, all of which varied significantly with age. General linear models suggested that pentosidine concentration and collagen content provided the best explanation of the age‐related decrease in the postyield energy dissipation. Among them, pentosidine concentration had the greatest contribution to plastic strain energy and was the best explanatory variable of damage accumulation. © 2007 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 25:646–655, 2007

Fracture risk does not solely depend on strength but also on fracture toughness; ie, the ability of bone material to resist crack initiation and propagation. Because resistance to crack growth largely depends on bone properties at the tissue level, including collagen characteristics, current X‐ray based assessment tools may not be suitable to identify age‐related, disease‐related, or treatment‐related changes in fracture toughness. To identify useful clinical surrogates that could improve the assessment of fracture resistance, we investigated the potential of ¹H nuclear magnetic resonance spectroscopy (NMR) and reference point indentation (RPI) to explain age‐related variance in fracture toughness. Harvested from cadaveric femurs (62 human donors), single‐edge notched beam (SENB) specimens of cortical bone underwent fracture toughness testing (R‐curve method). NMR‐derived bound water showed the strongest correlation with fracture toughness properties (r = 0.63 for crack initiation, r = 0.35 for crack growth, and r = 0.45 for overall fracture toughness; p < 0.01). Multivariate analyses indicated that the age‐related decrease in different fracture toughness properties were best explained by a combination of NMR properties including pore water and RPI‐derived tissue stiffness with age as a significant covariate (adjusted R² = 53.3%, 23.9%, and 35.2% for crack initiation, crack growth, and overall toughness, respectively; p < 0.001). These findings reflect the existence of many contributors to fracture toughness and emphasize the utility of a multimodal assessment of fracture resistance. Exploring the mechanistic origin of fracture toughness, glycation‐mediated nonenzymatic collagen crosslinks and intracortical porosity are possible determinants of bone fracture toughness and could explain the sensitivity of NMR to changes in fracture toughness. Assuming fracture toughness is clinically important to the ability of bone to resist fracture, our results suggest that improvements in fracture risk assessment could potentially be achieved by accounting for water distribution (quantitative ultrashort echo time magnetic resonance imaging) and by a local measure of tissue resistance to indentation, RPI. © 2015 American Society for Bone and Mineral Research.