Abstract:

Over the last 30 years, bisphosphonates (BP) have been shown to be extremely effective in the treatment of bone diseases characterized by excessive bone resorption, such as osteoporosis. The structure of these nonhydrolyzable analogues of naturally occurring inorganic pyrophosphate, characterized by a carbon bridging two phosphonate residues, allows for enhancement of this affinity by changing the two lateral groups bound to the central carbon; the R 1 and R2 ligands. Extensive research into the structure-activity relationship has determined the conditions for the P-C-P moiety and R 1 to achieve optimal binding of the drug to bone surfaces. It is generally held that the primary function of the R2 is cellular, rather than physiochemical. However, in vitro constant composition studies have shown significant variation in the inhibition of apatite growth and dissolution for bisphosphonates that differ only in their R2 functionality.

In this thesis, a series of BPs were used to study the effects of R 2 structure on the inhibition of hydroxyapatite (HAP) growth on synthetic HAP and natural bone samples using the constant composition (CC) method at physiological ionic strength and temperature. Significant differences in inhibitory capacity and kinetic adsorption affinity were observed for BP structural analogs, with minor differences in their respective R2 structures and orientations. These differences were observed for both synthetic and natural apatite experiments. The influence of R2 on the zeta potential of HAP and Brushite (DCPD) was also investigated. The results suggest that weak hydrogen bonding may be occurring between nitrogen containing R2 groups and the apatite surface, depending on the structure and orientation of the lateral group.

These results provide considerable insight into the physiochemical importance of the R2 group during BP adsorption to the apatite surface in vitro , greatly adding to our understanding of the BP structure-activity relationship and its role in the adsorption of these drugs in vivo .