Effects of Aging and Disuse on Bone Remodeling in Response to Microdamage.

The risk of whole bone fracture in osteoporosis may be substantially increased as a result of microdamage accumulation in bone in conjunction with the associated remodeling that attempts to repair the damage. The risk may be increased as a result of age and disuse, which are hypothesized to alter remodeling in response to microdamage. Elucidating the effects of age and disuse on bone repair may provide clinically important insight into the relationship between microdamage accumulation and increased fracture risk in the elderly. The goals of this study were to experimentally determine the influence of age and mechanical usage on microdamage accumulation and repair. A unique animal model was developed that enabled loading of distal femoral trabecular bone of rats in-vivo. Utilizing this model, older rats (compared with adults) demonstrated a reduced ability of bone to recover after damage and a reduction in the removal of microdamage. For the second series of studies a hindlimb suspension system and four-point bending apparatus were developed to simulate disuse and induce tibial cortical microdamage. Utilizing these models, it was shown that disuse alters the bone’s response to microdamage through a reduction in woven bone production and cessation of microdamage resorption. Finally, it was shown that daily short-term weight-bearing during disuse rescued the targeted bone remodeling response following microdamage induction. These findings suggest that individuals with severe activity reductions may further accumulate microdamage. Most importantly, while many studies have proposed that microdamage repair is triggered by cell apoptosis, our present results suggest this mechanism may be insufficient without the stimulus associated with mechanical usage. In addition, the ability to rescue the remodeling response through intermittent physiologic loading provides support to early clinical evidence that moderate loading can reduce recovery time from stress fractures. In aggregate, advanced age and disuse were shown to lead to a reduction in targeted remodeling associated with microdamage. This could potentially increase fracture risk due to potential microdamage accumulation. In addition, the importance of physiological loading to the process of microdamage repair suggests that the current clinical practice of limiting weight-bearing for the treatment of stress fractures should be reconsidered.Ph.D.Biomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/61648/1/ewaldorf_1.pd

Microdamage repair and remodeling requires mechanical loading

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 ResearchPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71374/1/91016_ftp.pd