Relative binding affinities of bisphosphonates for human bone and relationship to antiresorptive efficacy

Potent bisphosphonates (BPs) preferentially bind bone at sites of active osteoclastic bone resorption, where they are taken up by the osteoclast and inhibit resorption. We tested the hypothesis that BP affinity to human bone affects antiresorptive potency. [C-14]-Alendronate binding to human bone was saturable and reversible with an apparent Kd of 72 mu M by Scatchard analysis. In competition binding assays, unlabeled alendronate (Ki: 61 mu M) was slightly more potent than pyrophosphate (Ki = 156 mu M) in blocking [C-14]-alendronate binding. Likewise, most tested BPs, including etidronate (Ki: 91 mu M), ibandronate (116 mu M), pamidronate (83 mu M), risedronate (85 mu M) and zoledronate (81 mu M), showed comparable affinities. Interestingly, tiludronate (173 mu M; P < 0.05 vs. all other BPs) and especially clodronate (806 mu M; P > 0.0001 vs. all other BPs) displayed significantly weaker affinity for bone. The weak affinity of clodronate translated into a requirement for 10-fold higher dosing in in vitro bone resorption assays when bone was pretreated with BP and subsequently washed prior to adding osteoclasts. In stark contrast, neither alendronate nor risedronate lost any efficacy after washing the bone surface. These findings suggest that most clinically tested BPs may have similar affinities for human bone. For those with reduced affinity, this may translate into lower potency that necessitates higher dosing. (c) 2005 Elsevier Inc. All rights reserved.