Abstract
Bone remodeling is necessary to avoid microdamage accumulation, which could lead to whole-bone failure. Previous studies have shown that this bone-repair mechanism is triggered by osteocyte apoptosis. Through the use of a rodent hindlimb suspension model and tibial four-point bending model, the effects of disuse on microdamage remodeling was examined. At day 0, male rats were assigned to one of three groups: weight bearing (WB), hindlimb suspension (HS), or hindlimb suspension with daily intermittent weight bearing following damage-inducing loading (HW). Within each group, the rats were further divided into subgroups corresponding to three sacrifice time points [day 14 (WB and HS only), day 18, or day 35]. At day 14, animals were anesthetized, and their left tibiae underwent cyclic four-point bending to produce fatigue-induced microdamage. At sacrifice, the tibiae were examined using 3D micro-computed tomography (µCT), flow cytometry, and histologic and immunohistochemical stains. The results indicate that only the WB and HW groups had a significant increase in intracortical TRAP-positive resorption pits following damage induction, which was paralleled by a significant decrease in microdamage over time in combination with a shift in the osteoclast lineage owing to a decrease in monocytes. These results demonstrate that osteocyte apoptosis may be insufficient for repair of microdamage without the stimulation provided through physiologic loading. In addition, this potentially could have clinical implications for the current therapeutic paradigm for treating stress fractures, where extended non-weight bearing is employed. © 2010 American Society for Bone and Mineral Research.
Highlights
IntroductionOsteoporotic fracture is a common and expensive health care problem, with 1.5 million fractures in the United States per year, with a predicted cost of $60 billion annually in the United States by 2025.(1) Yet the factors responsible for susceptibility to fracture remain incompletely understood.The existence of microdamage within bone has been reported to induce localized osteocyte apoptosis surrounding individual microcracks,(2,3) which subsequently leads to targeted remodeling.[2,4,5,6,7,8,9] It has been proposed that whole-bone failure in osteoporosis may be a result of positive feedback between microdamage and the resulting remodeling that attempts to repair the damage.[10]
Mineralization increased for all groups, but with the weight bearing (WB) group having significantly more woven bone deposited than the hindlimb suspension (HS) and HW groups (Fig. 1B), leading to a larger cross-sectional area (Fig. 1A)
The damage response corresponds to what has been shown in previous animal models, where fatigue loading induced woven bone formation that was both dependent on and proportional to the amount of induced microdamage.[43,44,46] Periosteal woven bone formation after fatigue damage has been shown to aid in the rapid recovery of whole-bone strength while increasing fatigue life.[44,47] does a significant amount of damage remain in animals that were hindlimb suspended, but the protective mechanism of woven bone formation was not present, suggesting that whole-bone strength remains low in a disuse setting following fatigue damage even with daily shortterm physiologic loading
Summary
Osteoporotic fracture is a common and expensive health care problem, with 1.5 million fractures in the United States per year, with a predicted cost of $60 billion annually in the United States by 2025.(1) Yet the factors responsible for susceptibility to fracture remain incompletely understood.The existence of microdamage within bone has been reported to induce localized osteocyte apoptosis surrounding individual microcracks,(2,3) which subsequently leads to targeted remodeling.[2,4,5,6,7,8,9] It has been proposed that whole-bone failure in osteoporosis may be a result of positive feedback between microdamage and the resulting remodeling that attempts to repair the damage.[10]. The reduced stiffness and strength may result in further damage or overt failure at lower loads than those required in the original intact bone, resulting in a positive-feedback process. This potentially could have important clinical implications. The relationship between microdamage accumulation and resorption may explain a portion of the increase in fracture risk in the elderly population. Whole-bone fracture risk potentially may increase if remodeling is altered. Aside from the alterations in remodeling activity owing to age,(11) bone loss associated with aging may result from disuse owing to reductions in physical activity or infirmity
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