The structure of human cortical bone evolves over multiple length scales from its basic constituents of collagen and hydroxyapatite at the nanoscale to osteonal structures at near-millimeter dimensions, which all provide the basis for its mechanical properties. To resist fracture, bone’s toughness is derived intrinsically through plasticity (e.g., fibrillar sliding) at structural scales typically below a micrometer and extrinsically (i.e., during crack growth) through mechanisms (e.g., crack deflection/bridging) generated at larger structural scales. Biological factors such as aging lead to a markedly increased fracture risk, which is often associated with an age-related loss in bone mass (bone quantity). However, we find that age-related structural changes can significantly degrade the fracture resistance (bone quality) over multiple length scales. Using in situ small-angle X-ray scattering and wide-angle X-ray diffraction to characterize submicrometer structural changes and synchrotron X-ray computed tomography and in situ fracture-toughness measurements in the scanning electron microscope to characterize effects at micrometer scales, we show how these age-related structural changes at differing size scales degrade both the intrinsic and extrinsic toughness of bone. Specifically, we attribute the loss in toughness to increased nonenzymatic collagen cross-linking, which suppresses plasticity at nanoscale dimensions, and to an increased osteonal density, which limits the potency of crack-bridging mechanisms at micrometer scales. The link between these processes is that the increased stiffness of the cross-linked collagen requires energy to be absorbed by “plastic” deformation at higher structural levels, which occurs by the process of microcracking.

Like bone mass, bone quality is specified in development, actively maintained postnatally, and disrupted by disease. The roles of osteoblasts, osteoclasts, and osteocytes in the regulation of bone mass are increasingly well defined. However, the cellular and molecular mechanisms by which bone quality is regulated remain unclear. Proteins that remodel bone extracellular matrix, such as the collagen‐degrading matrix metalloproteinase (MMP)‐13, are likely candidates to regulate bone quality. Using MMP‐13–deficient mice, we examined the role of MMP‐13 in the remodeling and maintenance of bone matrix and subsequent fracture resistance. Throughout the diaphysis of MMP‐13–deficient tibiae, we observed elevated nonenzymatic cross‐linking and concentric regions of hypermineralization, collagen disorganization, and canalicular malformation. These defects localize to the same mid‐cortical bone regions where osteocyte lacunae and canaliculi exhibit MMP‐13 and tartrate‐resistant acid phosphatase (TRAP) expression, as well as the osteocyte marker sclerostin. Despite otherwise normal measures of osteoclast and osteoblast function, dynamic histomorphometry revealed that remodeling of osteocyte lacunae is impaired in MMP‐13^−/− bone. Analysis of MMP‐13^−/− mice and their wild‐type littermates in normal and lactating conditions showed that MMP‐13 is not only required for lactation‐induced osteocyte perilacunar remodeling, but also for the maintenance of bone quality. The loss of MMP‐13, and the resulting defects in perilacunar remodeling and matrix organization, compromise MMP‐13^−/− bone fracture toughness and postyield behavior. Taken together, these findings demonstrate that osteocyte perilacunar remodeling of mid‐cortical bone matrix requires MMP‐13 and is essential for the maintenance of bone quality. © 2012 American Society for Bone and Mineral Research.