Repair mechanisms for microdamage in bone.

When Harold Frost first identifiedmicrodamage generated in vivo in bone, hewas referring only to linearmicrocracks that were discrete and whose edges could be identified microscopically. Whether these were real or artifactual was a source of debate for many years until, in the early 1990s, more than a few laboratories had observed them using Frost’s en bloc staining technique. A veritable feeding frenzy of microdamage‐ related research ensued as the scientific community attempted to understand how linear microcracks affected the mechanical properties of bone and whether they were a stimulus for the initiation of bone remodeling and self‐repair. Now, Seref‐ Felenguez and colleagues present the first quantitative data to show conclusively that diffuse damage can be repaired directly in vivo, without the intervening step of bone remodeling. It was well known from the materials and engineering literature that microscopic cracks in materials grew by developing smaller secondary cracks at the front of the developing linear microcrack where the stresses are high, a region known as the damage process zone. This suggested that damage could occur at different levels and size scales. However, damage at smaller size scales was not really recognized as an entity unto itself until the later 1990s, when several groups began to identify regions of diffuse staining that were found to be associated with collections of very small (<10mm) cracks, initially identified by confocal microscopy. It was later determined that diffuse damage occurs well below the lamellar length scale (1 to 3mm) and perhaps even at the level of the collagen fibril ( 1mm). Boyde tended to dismiss these observations, stating that “ultra‐microcracks (Fazzalari and colleagues, 1998a) need not be other than, perhaps exaggerated, normal fine structural boundaries within the hard tissue matrix.” Nevertheless, these small cracks were considered by many to be the precursors to larger linearmicrocracks, which were thought to be formed in part by coalescence of these smaller cracks. Subsequent work showed that although diffuse damage and linear microcracks could co‐occur, they most often were associated with different kinds of mechanical stress, and occurred preferentially in different age groups. Using ex vivo cyclic bending tests of human cortical bone from the tibia, Boyce and colleagues showed that diffuse damage was more prominent within tensile cortices, but longer linear microcracks were localized to compressive cortices. The following year, Reilly and Currey confirmed these observations, as did Diab and Vashishth several years later. This compartmentalization of damage types to specific strain modes made it much less likely that diffuse damage was the precursor for linear microcracks, raising the possibility, then, that the repair of these two types of damagemight also be distinct. Moreover, bone from younger donors had a longer fatigue life and more diffuse damage than bone from older donors, whereas older donors tended to form more linear microcracks. This suggested, and was later confirmed, that diffuse damage dissipates more energy than linear microcracks and allows for a longer fatigue life. Moreover, Diab and Vashishth demonstrated that the in vivo incidence of diffuse damage in human cortical bone decreases with age. Thus, in vivo mechanisms may exist to repair diffuse damage and/or older bone loses it propensity to form diffuse damage. It had become clear by the late 1990s that linear microcracks were a stimulus for bone remodeling, an idea originally proposed by Frost. The signaling mechanism that allowed the cells to identify the damage and mount a repair response was uncertain. Frost deduced that the microcrack must disrupt canalicular communication among osteocytes, and proposed this as the stimulus. This insight was not far afield as the damage to the canaliculi likely stimulates the death of osteocytes by apoptosis. When osteocyte apoptosis is prevented by caspase inhibitors, remodeling does not occur, confirming the vital role played by osteocyte apoptosis in the signaling mechanism. When damage is induced in bone, the ratio of receptor activator of NF‐kB ligand/osteoprotegerin (RANKL/OPG) increases several‐ fold; this is probably the signal for osteoclast differentiation and recruitment. This increase in RANKL does not occur from the apoptotic osteocytes but rather from adjacent vital osteocytes. Recently, Kennedy and colleagues showed that preventing the apoptosis of osteocytes near fatigue‐induced damage prevents the upregulation of RANKL in the viable osteocytes in the penumbra region, indicating that osteocyte apoptosis not only is critical for repair of damage but also that the dying osteocytes communicate with adjacent viable osteocytes that actually orchestrate the signals for repair. For many years, diffuse damage was suspected by many to be repaired in a similar manner, through whole‐bone remodeling. However, the localization of diffuse and linear damage to different compartments of the bone and the limited canalicular damage created by the very small sublamellar diffuse cracks did not make this at all certain. Herman and colleagues tested this