Interactions between Clinically Used Bisphosphonates and Bone Mineral: from Coordination Chemistry to Biomedical Applications and Beyond

Abstract

Bisphosphonates (BPs) are well-established, widely used first-choice drugs for bone-related diseases and are one of the few classes of molecules for selective bone targeting. Their binding to calcium cations within hydroxyapatite (HA) is a key physicochemical event that takes place on the bone surface. It is the starting point for a cascade of biochemical reactions and cellular effects that lead to the pharmacological activity of BPs. The phenomenon has been known for years, yet its physicochemical nature is still not fully understood. In particular, the adsorption/release processes and structure-function relationships of BPs remain to be clarified. These are elementary, yet crucial factors, which should influence the design and development of new delivery tools or drugs with improved characteristics. This review summarizes the current understanding of the chemical interactions between clinically used BPs and bone mineral, starting from basic Ca coordination chemistry through to interactions with hydroxyapatite, nanocrystalline apatites, and natural bone mineral.

Thermodynamics of the Interactions of Aminobisphosphonates and Their Calcium Complexes with Bovine Serum Albumin

“…In basic pH, CaL complexes (for all studied ligands) undergo one step hydrolysis to CaH –1 L (Ca(OH)L) species; the p K s of these processes lie in the range of 9.91 – 10.17 and can be assigned to deprotonation of water molecules bound to Ca 2+ . Undoubtedly, neither NH + R nitrogen nor RNH 3 + moieties do not participate in metal ion binding, in contrast to e.g., Cu 2+ , which has been found in many examples of N‐BPs both in solution and solid state . Proposed coordination models for inc and L 2 do not differ significantly from coordination of L 1 , what leads us to an assumption that the binding is implemented in the same manner with using phosphonic functions of the ligands only.…”

“…In basic pH, CaL complexes (for all studied ligands) undergo one step hydrolysis to CaH -1 L (Ca(OH)L) species; the pKs of these processes lie in the range of 9.91 -10.17 and can be assigned to deprotonation of water molecules bound to Ca 2+ . Undoubtedly, neither NH + R nitrogen nor RNH 3 + moieties do not participate in metal ion binding, [3] [20] in contrast to e.g., Cu 2+ , [32] [39] which has been found in many examples of N-BPs both in solution and solid [39] Due to very basic constants of amine functions NH + R, which do not deprotonate in measurable range of pH for inc and L 1 correct notification should be: inc = Hinc and L 1 = HL, however, here it was omitted for simplicity as suggested for analogous compounds in the literature. [40] [b] Obtained using Hyss2009 program, based on traditional approach introduced by Schwarzenbach, [41] state.…”

“…[20] [40] Ranks of logb values of CaL and CaL 2 complexes are as follows: 4.56 (inc), 4.86 (L 1 ), and 5.66 (L 2 ), and 8.52 (inc), 8.59 (L 2 ), and 8.93 (L 1 ), respectively; suggesting similar abilities of studied ligands to bind calcium cations in comparison to each others as well as other aminobisphosphonates, including those of medical use. [3][43] [44] However, when calculating logarithms of conditional stability constants (logK c ) at fixed pH 7.4 with respect to CaL, this rank is the opposite: 4.53 (inc), 4.00 (L 1 ), and 3.49 (L 2 ) and is in fact a better reflection of real binding strength, independent from co-existence of different species in the solution. The complexation process of L 1 was described in details in our previous studies [32] and assumed purely oxygen coordination of Ca 2+ .…”

“…Bisphosphonates (BPs) are a class of bone‐targeting drugs that have been used extensively in the treatment of bone‐resorptive diseases: osteoporosis, malignancy‐related hypercalcemia, Pagets disease, etc . BP drugs are divided into two subclasses characterized by a different mechanism of antiresorptive action and the rate of activity: i) non‐amino‐containing bisphosphonates (NN‐BP); less potent that are metabolized to cytotoxic analogs of adenosine triphosphate in the cell, and ii) amino‐containing bisphosphonates (N‐BP) ‐ considered as more potent due to the ability of inhibition of the mevalonate pathway enzyme farnesyl diphosphate (FPP) synthase in osteoclasts that leads to their apoptosis …”

Investigation of 177Lu-labeled HEDP, DPD, and IDP as potential bone pain palliation agents

“…Surprisingly, a biodistribution study revealed that among examined radiolabeled complexes, only 177 Lu-HEDP has high bone uptake. This can be explained by the significant role of hydroxyl group which enhanced chemisorptions of OH-phosphonates, possible formation of tridentate complex and more stable binding to Ca 2+ (Gałęzowska, 2018;Palma et al, 2011). The bone uptake of the activity was observed 0.5 h post-injection and it became quite significant at 2 h. At this time point, the total skeleton was clearly visible with an insignificant accumulation of activity in any soft tissues.…”