The role of the osteoclast during endochondral ossification in a rat fracture model
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Bisphosphonates (BPs) are the most common treatment for osteoporosis, due to their powerful ability to inhibit osteoclastic bone resorption. They are also being investigated to augment callus production during fracture healing, however, concerns exist as to the effects of BPs during both initial fracture union and hard callus remodelling. Endochondral ossification during fracture repair is a critical process leading to initial union, and is assumed to be dependent on osteoclast function. Hard The role of osteoclasts during initial endochondral fracture union was investigated using the BP zoledronic acid (ZA) and in a genetic model of osteoclast inactivity, the incisor absent (ia/ia) rat. In addition, the effect of differing ZA treatment regimes on hard callus remodelling was investigated using both Bolus and Weekly ZA dosing. A Bolus of 0.1mg/kg ZA or 5 Weekly doses of 0.02mg/kg ZA or Saline were administered commencing 1 week post surgery in a rat femoral fracture model. Femoral fractures were also produced in ia/ia rats. Examinations were performed up to initial union and throughout callus remodelling. ZA treatment did not alter the rate of endochondral fracture union. All fractures united by 6 weeks, with no difference in the percentage of cartilaginous callus between treatment groups at any time point. Fracture union was achieved by 3 weeks in both ia/ia and control rats, again with no difference in the percentage of cartilaginous callus. In contrast, marked differences in hard callus were evident in the ZA treated groups. ZA increased callus bone mineral content, volume and importantly increased callus strength. Bolus ZA treatment did not delay the commencement of hard callus remodelling at 4 weeks post fracture, whereas this was delayed in the Weekly ZA group. By 12 and 26 weeks Bolus ZA had the same callus content of remodelled neo-cortical bone as Saline, however Weekly ZA had significantly less than saline at these times. These extensive delays in hard callus remodelling with Weekly ZA dosing produced a fracture callus of inferior material properties. In conclusion, neither ZA treatment nor the absence of active osteoclasts in ia/ia rats delayed endochondral fracture union. Thus, this study confirms the redundancy of osteoclasts in this process. Bolus ZA treatment was superior to Weekly ZA dosing; hard callus remodelling proceeded, producing a strong fracture callus with improved material properties. This study supports the use of less frequent ZA doses during fracture repair.callus remodelling, known to be dependent on osteoclast function, is important to the completion of bone repair.
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