113. Association biphosphonate-calcium phosphate injectable dans le traitement percutané des résorptions osseuses pathologiques - Design of injectable bisphosphonate - calcium phosphate cement combinations for the local treatment of bone pathological resorption

B. Bujoli, J-M. Bouler, P. Janvier, I. Khairoun, V. Schnitzler (Nantes, France)

INTRODUCTION: Many groups in industry and academia worldwide are actively developing drug/medical device combination products for local drug therapies and infection prophylaxis. The use of such combined devices in orthopedics represents an emerging promising field, in particular for those based on calcium phosphates (CaP). In this context, calcium phosphate cements (CPCs) have been considered as carriers for local and controlled supply of various drugs, thus potentially providing a reliable means of producing efficient pharmacological effects only to specifically intended target sites. In particular, such an approach could be of interest in the case of osteoporosis.

METHODS: The optimized CPC formulation had the following composition for the solid phase: a-TCP (Ca3(PO4)2, 78 wt%), DCPD (CaHPO4.2H2O, 5 wt%), MCPM (Ca(H2PO4)2.H2O, 5 wt%), 0.67wt% alendronate-doped CDA (Ca10-x[ ]x(HPO4)y(PO4)6-y(OH)2-z[ ]z, 10 wt%) prepared as reported previously1, hydroxypropyl methyl cellulose [HPMC] (2 wt%). The liquid phase consists in a 5 wt% Na2HPO4 solution, with a liquid/powder ratio of 0.5 mL g-1.

RESULTS: Our purpose was to design an injectable CPC-based medical device capable of providing mechanical bone reinforcement and delivering bisphosphonate BP antiresorptive drugs, for the prevention of the osteoporotic fracture. Indeed, cement augmentation of the proximal femur by minimally invasive surgery (femoroplasty) may increase mechanical stability and reduce fracture risk as the primary effect, in addition to the ancillary action of the BP itself. Accordingly, we have examined whether BPs (e.g. Alendronate) can be incorporated in a CPC cement, without affecting the properties of the curing and cured cement (injectability, setting time, resorbability, strength). Various Alendronate-loading (up to 0.40 wt% with respect to the solid phase) were investigated, for which the BP was introduced under five different conditions: (i) dissolved in the liquid phase (ii) added to the ground solid phase (iii) or combined to one of the calcium phosphate components of the solid phase (i.e. a-TCP, CDA, DCPD).

CONCLUSIONS: Not surprisingly, the Alendronate doping increases the setting time at 20_C regardless and independent of the method used for its incorporation, while this trend becomes more and more significant as the BP-loading increases. However, the retarding effect of the BP on the setting time was found to be limited when combined to CDA. Accordingly, an optimized CPC formulation2 (see experimental method) was thus obtained, showing a short cohesion time along with setting times appropriate for pre-clinical uses (initial setting time (37_C): 5-7 min.; final setting time (37_C): 15-18 min.). Cement augmentation of the proximal femur was performed with this BP-loaded CPC, using an osteoporosis animal model (ewe), and investigation of the in vivo properties of the implant is currently under progress.

REFERENCES: 1- Roussiere, H.; Montavon, G.; Samia, L. B.; Janvier, P.; Alonso, B.; Fayon, F.; Petit, M.; Massiot, D.; Bouler, J. M.; Bujoli, B. J. Mater. Chem. 2005, 15, 3869.
2- Bouler, J.-M.; Bujoli, B.; Janvier, P.; Khairoun, I.; Argenson, J.-N. Patent WO2008098959 (2008-08-21).

ACKNOWLEDGEMENTS: This work was supported by ANR “RNTS 2005” and the Graftys company.

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