The Bisphosphonates Clodronate and Etidronate Exert Analgesic Effects by Acting on Glutamate- and/or ATP-Related Pain Transmission Pathways

Abstract

Key words analgesic effect; clodronate; etidronate; phosphate transporter; ATP; glutamate Bisphosphonates (BPs) are used against various boneresorptive diseases, and the nitrogen-containing BPs (N-BPs) have much more powerful anti-bone-resorptive effects than the non-nitrogen-containing BPs (non-N-BPs) 1) (Fig. 1). However, N-BPs have inflammatory and/or necrotic effects, including fever, musculoskeletal pain, direct injuries to esophageal and gastric tissues, and osteonecrosis of the jaw.2) N-BPs, having entered cells (including osteoclasts), exhibit cytotoxicity due to inhibition of farnesyl pyrophosphate synthase in the mevalonate pathway of cholesterol biosynthesis, 1) reducing the prenylation of various proteins, including small guanosine 5′-triphosphatase (GTPases). 3)In contrast to N-BPs, the non-N-BPs etidronate and clodronate are almost devoid of inflammatory/necrotic effects. 4)Interestingly, they can reduce such side effects of N-BPs in mice. [5][6][7][8] Concerning the mechanisms by which clodronate (Clo) and etidronate (Eti) reduce the inflammatory/necrotic effects of N-BPs, our pharmacological studies have suggested that: (a) N-BPs may enter soft-tissue cells via phosphate transporters of the SLC20 and SLC34 families, (b) Clo and Eti may inhibit those families, possibly by competitive inhibition, and thereby inhibit the entry of N-BPs into soft-tissue cells, and (c) Clo and Eti may also inhibit phosphate transporters of the SLC17 family. 9)Pain is a cause of distress in many patients with osteoporosis. Fujita et al. found that in patients with osteoporosis and/ or osteoarthritis, Eti displayed an analgesic effect that was greater than those of N-BPs. 10) We recently reported that Clo and Eti exhibit analgesic effects in mice, possibly via direct interaction with neurons. 11) However, the mechanism underlying the analgesic effects of Clo and Eti remains unclear.Surprisingly, and very interestingly, the SLC17 family of transporters, initially characterized as phosphate carriers, was recently found to include neuronal vesicular transporters of glutamate and ATP. [12][13][14][15] The N-methyl-D-aspartate (NMDA) receptor (NMDA-R), an ionotropic receptor for glutamate, is distributed within the spinal cord and plays an important role in pain transmission. [16][17][18] In addition, nucleotides are released or leaked from non-excitable cells, as well as neurons, under both physiological and pathophysiological conditions, and recent studies indicate that ATP plays important roles during pain transmission through the ionotropic purinoceptor P2X-R. 19,20) There are as yet no reports describing relationships between BPs and neuronal transmitters. However, on the basis of the findings described above, we hypothesized that Clo and Eti may enter neurons through SLC20 and/or SLC34, and then act on neuronal vesicles to inhibit SLC17 transporter-mediated transport of glutamate and/or ATP (resulting in decrements in the levels of glutamate and ATP within the vesicles) (Fig.

Inflammatory Effects of Nitrogen-Containing Bisphosphonates (N-BPs): Modulation by Non-N-BPs

“…Clo and Eti exert analgesic effects via inhibition of phosphate transporters of the SLC17 family. 37) Those findings, together with the ones made in the present study, may suggest that Eti and Clo should be reappraised as safe and useful drugs for osteoporosis.…”

Underlying Mechanisms and Therapeutic Strategies for Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ)

“…86) Thus, it is likely that Eti and Clo exhibit their analgesic effects by inhibiting these transporters. Indeed, our recent study supports this idea 17) (Fig. 6).…”

Augmentation of Lipopolysaccharide-Induced Production of IL-1α and IL-1β in Mice Given Intravenous Zoledronate (a Nitrogen-Containing Bisphosphonate) and Its Prevention by Clodronate (a Non-nitrogen-containing Bisphosphonate)

“…injected N-BPs tested (4 mM) are reduced by co-injection with clodronate (1-16 mM), 20) and that the inflammatory and/or necrotic effects of locally injected N-BPs, including zoledronate, are likewise reduced by co-injection with clodronate. 18,19,21,22) So, we compared the effects of clodronate on the augmented production of IL-1α and IL-1β seen in mice given i.v. zoledronate and then (3 d later) i.v.…”

“…Effect of Clodronate on the Increased IL-1α and IL-1β Production Induced by Zoledronate Plus LPS Our pharmacological results suggest that N-BPs may enter soft-tissue cells via the phosphate transporter families SLC20 and/or SLC34, and that clodronate inhibits this entry and thereby reduces or prevents the inflammatory and/or necrotic effects of N-BPs. 21,22) SLC20 transporters are known to be present ubiquitously throughout the body. 32,33) In the present study, we found that 20 mM clodronate, when co-injected with 4 mM zoledronate, can reduce the augmented production of IL-1α and IL-1β in bone and spleen induced when i.v.…”

“…injected N-BPs induce various inflammatory reactions, including the production of interleukin-1 (IL-1) (a typical inflammatory cytokine with a pyrogenic action) in various soft tissues (such as liver, spleen, and lung), [11][12][13][14][15] and that such inflammatory reactions are weak in IL-1-deficient mice, 13,16) (ii) lipopolysaccharide (LPS, a cell-wall component of Gram-negative bacteria) and N-BPs mutually augment their inflammatory effects, [13][14][15]17) (iii) locally injected N-BPs induce inflammation and/or necrosis at the injection sites when given at a high concentration, 18,19) (iv) the non-N-BP clodronate can reduce or prevent the systemic and local inflammatory/necrotic effects of N-BPs [18][19][20][21] by inhibiting the intracellular uptake of N-BPs through phosphate transporters. 3,[21][22][23][24] As described above, the acute inflammatory side effects of N-BPs occur after intravenous (i.v.) injection.…”