title: Relative binding affinities of bisphosphonates for human bone and relationship to antiresorptive efficacy.
abstract: 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. [(1)(4)C]-Alendronate binding to human bone was saturable and reversible with an apparent Kd of 72 microM by Scatchard analysis. In competition binding assays, unlabeled alendronate (Ki: 61 microM) was slightly more potent than pyrophosphate (Ki = 156 microM) in blocking [(1)(4)C]-alendronate binding. Likewise, most tested BPs, including etidronate (Ki: 91 microM), ibandronate (116 microM), pamidronate (83 microM), risedronate (85 microM) and zoledronate (81 microM), showed comparable affinities. Interestingly, tiludronate (173 microM; P < 0.05 vs. all other BPs) and especially clodronate (806 microM; 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.
authors.affiliation: Department of Molecular Endocrinology and Bone Biology, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Chih-Tai
authors.initials: CT
authors.lastname: Leu
authors.forename: Eva
authors.initials: E
authors.lastname: Luegmayr
authors.forename: Leonard P
authors.initials: LP
authors.lastname: Freedman
authors.forename: Gideon A
authors.initials: GA
authors.lastname: Rodan
authors.forename: Alfred A
authors.initials: AA
authors.lastname: Reszka
mesh_terms: D019386:Alendronate / Q000378:metabolism* / Q000627:therapeutic use; D000818:Animals; D001667:Binding, Competitive; D050071:Bone Density Conservation Agents / Q000378:metabolism* / Q000627:therapeutic use; D001862:Bone Resorption / Q000188:drug therapy*; D001842:Bone and Bones / Q000378:metabolism*; D011756:Diphosphates / Q000378:metabolism; D004164:Diphosphonates / Q000378:metabolism* / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D051381:Rats
chemical_list: D050071:Bone Density Conservation Agents; D011756:Diphosphates; D004164:Diphosphonates; D019386:Alendronate