Differences between bisphosphonates in binding affinities for hydroxyapatite

Abstract

Bisphosphonates (BPs) inhibit bone resorption and are widely used for the treatment of bone diseases, including osteoporosis. BPs are also being studied for their effects on hydroxyapatite (HAP)-containing biomaterials. There is a growing appreciation that there are hitherto unexpected differences among BPs in their mineral binding affinities that affect their pharmacological and biological properties. To study these differences, we have developed a method based on fast performance liquid chromatography using columns of HAP to which BPs and other phosphate-containing compounds can adsorb and be eluted by using phosphate buffer gradients at pH 6.8. The individual compounds emerge as discrete and reproducible peaks for a range of compounds with different affinities. For example, the peak retention times (min; mean +/- SEM) were 22.0 +/- 0.3 for zoledronate, 16.16 +/- 0.44 for risedronate, and 9.0 +/- 0.28 for its phosphonocarboxylate analog, NE10790. These results suggest that there are substantial differences among BPs in their binding to HAP. These differences may be exploited in the development of biomaterials and may also partly explain the extent of their relative skeletal retention and persistence of biological effects observed in both animal and clinical studies.

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

“…The maximal amount of 3a bound to HA is much higher (nearly 1.5 to 1.9 fold) than those of 3b-e because of only a small difference in the substituent R 2 . As shown in the previous study, [26] when the risedronate was attached to an extra methyl group in the R2 side chain, the two BPs had different retention times (16.16 and 14.41 respectively) indicating the decrease of HA 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] Also, a method based on fast performance liquid chromatography (FPLC) uses columns of HA, to which BPs and other phosphate-containing compounds can adsorb and be eluted. [26] Even though these methods can qualify binding affinities, a more accurate, precise, and economic method should be developed. In the present work, to quantify the bone targeting efficiency of the BPs 3a]e, a new method was set up using HPLC which employs the most common detection system and the simplest chromatography elution conditions found in experimental and clinical laboratories.…”

A sugar-based phase-transitioning delivery system for bone tissue engineering

“…Bisphosphonates bind to bone and prevent resorption, although binding affinities can vary between bisphosphonates. In vitro assays have shown zoledronic acid (ZA) has a strong affinity for bone mineral (Lawson et al, 2010). The development of strategies that take into account bone resorption and take advantage of the anti-resorptive properties of bisphosphonates as well as their capacity to bind with high affinity to hydroxyapatite (HA) are a natural evolution for bone tissue engineering carriers.…”

Bases for the study of the safety of medicines. The spectrum of rare and unexpected ad-verse reactions of bisphosphonates

“…Степень связи различных БФ с гидроксиапатитом и фарнезилпиро-фосфатсинтазой отличается, что, по мнению некоторых ис-следователей [6][7][8], создает предпосылки для различий в эффективности и безопасности препаратов.…”