Abstract 22

ZOLEDRONIC ACID TREATMENT ENHANCES NET VASCULARIZED HARD CALLUS FORMATION IN A CLOSED RAT FRACTURE MODEL

McDonald MM, Dulai S, Godfrey C, Hamilton B, Little DG

The Children's Hospital at Westmead, Sydney, NSW, Australia

It has been assumed that osteoclast activity is a prerequisite for the normal process of endochodral ossification. However recent studies have suggested that endochondral ossification proceeds normally at the growth plate, even in the absence of osteoclasts. We therefore hypothesized that endochondral ossification (soft callus removal) during fracture repair would not be delayed by the potent osteoclast inhibitor zoledronic acid (ZA).

ZA dosing commenced in rats 1 week post closed fracture, with harvests at 2, 4 and 6 weeks. Dosing regimes included: saline, low dose 0.025 mg/kg ZA as bolus (LDB) or divided weekly doses (LDW), and high dose 0.1 mg/kg ZA as bolus (HDB) or divided weekly doses (HDW). Histomorphometry revealed no significant difference in the percent of avascular cartilaginous (soft) callus, regardless of treatment. All groups showed complete vascular ossification (hard callus) by 6 weeks.

QCT at 6 weeks revealed increases in callus BMC (p<0.01) and callus volume (p<0.05) in all ZA groups over saline. Between 4 and 6 weeks, HDB-ZA callus volume decreased by 8%, indicating remodelling was occurring. In contrast, HDW-ZA caused delayed remodelling, callus volume increasing by 24%.

In conclusion, ZA did not delay fracture callus endochondral ossification, indicating that osteoclast function is not essential to soft callus removal. Single dose bolus treatment provided a better outcome over continuous dosing, allowing for hard callus remodelling while still increasing callus BMC and volume. This study reveals that ZA treatment during fracture repair is clinically safe: it provides a larger hard callus without delaying endochondral ossification.

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