Abstract 33

DEVELOPING SUPERIOR IN VITRO MODELS OF BISPHOSPHONATE THERAPY

Schindeler A and Little DG.

The Children's Hospital at Westmead, Sydney Australia

Zoledronic acid (ZA) is a potent nitrogen-containing bisphosphonate (N-BP) used in the treatment of osteoporosis and diseases of high bone turnover. In vivo, ZA binds rapidly and strongly to the skeleton to suppress osteoclast-mediated bone resorption. Resorbing osteoclasts are able to release and internalise bone N-BP at the bone surface, however other non-resorbing cells may be incapable of achieving this. In fact, it was recently shown that J774 macrophages are unaffected by bound N-BP. Numerous in vitro studies have analysed the effects of ZA and other N-BPs on osteoblasts by treating the cell culture media with continuous drug doses. Nevertheless, these drug treatments may not be the most appropriate methods for reproducing the in vivo situation.

We have used several approaches to better model the effects of clinical dosing with ZA. Osteoblasts cultured on calcium phosphate-coated discs were not adversely affected by ZA treatment, indicating that drug uptake is indeed limited when ZA is bound. Thus the major exposure of osteoblasts to ZA will occur in the hours immediately following dosing. To model this, we exposed differentiating MC3T3-E1 osteoblasts briefly to ZA and then cultured them normally for 1-3 weeks. Osteoblasts proved highly resistant to all short ZA treatment regimes, even when utilising doses of ZA that prevented mineralisation and/or induced cell death when administered for prolonged periods (i.e. 10-50µM). These methods may lead to more physiologically relevant models of N-BP treatment being adopted in osteoblast culture systems.

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