Bisphosphonate binding affinity as assessed by inhibition of carbonated apatite dissolution in vitro

Abstract

Bisphosphonates (BPs), which display a high affinity for calcium phosphate surfaces, are able to selectively target bone mineral, where they are potent inhibitors of osteoclast-mediated bone resorption. The dissolution of synthetic hydroxyapatite (HAP) has been used previously as a model for BP effects on natural bone mineral. The present work examines the influence of BPs on carbonated apatite (CAP), which mimics natural bone more closely than does HAP. Constant composition dissolution experiments were performed at pH 5.50, physiological ionic strength (0.15M) and temperature (37°C). Selected BPs were added at (0.5 × 10 −6 ) to (50.0 × 10 −6 )M, and adsorption affinity constants, K L , were calculated from the kinetics data. The BPs showed concentrationdependent inhibition of CAP dissolution, with significant differences in rank order zoledronate > alendronate > risedronate. In contrast, for HAP dissolution at pH 5.50, the differences between the individual BPs were considerably smaller. The extent of CAP dissolution was also dependent on the relative undersaturation, σ, and CAP dissolution rates increased with increasing carbonate content. These results demonstrate the importance of the presence of carbonate in mediating the dissolution of CAP, and the possible involvement of bone mineral carbonate in observed differences in bone affinities of BPs in clinical use.

Bone material properties in actively bone-forming trabeculae in postmenopausal women with osteoporosis after three years of treatment with once-yearly Zoledronic acid

“…A potential explanation may lie in the reported properties of apatite following bisphosphonate adsorption. (34,35) Among bisphosphonates currently used as osteoporosis therapies, ZOL not only has the highest affinity for apatite crystals but also is the only agent that exhibits a negative zeta potential once adsorbed at pH 7.4. Cells in general do sense and react to electrochemical potential; thus it is plausible that despite the high affinity that ZOL has for apatite surfaces, the negative zeta potential of these crystals after adsorption somehow influences osteoblastic function (via a qualitative rather than a quantitative effect) and/or mineralization commencement and mineral crystallite maturation kinetics as crystals of lower maturity/crystallinity are encountered.…”

An in vitro Assay to Measure Targeted Drug Delivery to Bone Mineral

“…[8] Major differences in bone binding affinity could potentially affect the pharmacokinetics and pharmacodynamics of bisphosphonate drugs, [1,2,9,10] and it is therefore important to measure their affinity for bone and to understand the structural details of binding. [11][12][13] Recently, determinations of bisphosphonate binding affinity for bone powder or HAP have been reported from in vitro assays that have been set up in three formats: 1) a radioactive competition assay using 14 C-alendronate, [14] 2) inhibition of HAP crystal growth using a constant composition method, [15,16] and 3) retention of small molecules on a HAP column as measured by FPLC. [17] Each of these methods has its advantages and drawbacks, and because the rank order of bisphosphonates is not identical across these assays, an independent method is valuable, especially if it is robust and generally applicable to a wide range of binding affinities.…”

A Series of Imidazolyl-Containing Bisphosphonates with Abundant Hydrogen-Bonding Interactions: Syntheses, Structures, and Bone-Binding Affinity

“…As detected by a constant composition potentiostatic method, Nancollas et al demonstrated significant differences in the binding affinity of similar BPs to HA and carbonated apatite and established a rank order of ibandronate , alendronate , pamidronate. [7,27,28] So, the results further demonstrate that the nature of the R 2 side chain has a significant influence on the binding affinity although they share a common P-C-P structure and OH at the R 1 side chain. On the other hand, it is known that small differences in the R 2 group lead to substantial changes in the 3D shapes and atomic orientations of the BPs according to the above single-crystal XRD studies.…”