Neuropharmacology and analgesia
Analgesic effects of the non-nitrogen-containing bisphosphonates etidronate and clodronate, independent of anti-resorptive effects on bone

https://doi.org/10.1016/j.ejphar.2012.11.031Get rights and content

Abstract

Nitrogen-containing bisphosphonates (NBPs) have greater anti-bone-resorptive effects than non-nitrogen-containing bisphosphonates (non-NBPs). Hence, NBPs are the current first-choice drug for osteoporosis. However, NBPs carry a risk of osteonecrosis of jaws. Some animal and human studies suggest that non-NBPs may have anti-bone-resorptive effect-independent analgesic effects, but there has been no detailed comparison between NBPs and non-NBPs. Here, we compared the analgesic effects of several non-NBPs and NBPs, using (a) writhing responses induced in mice by intraperitoneal injection of 1% acetic acid, (b) acetic acid-induced neuronal expression of c-Fos, (c) acetic acid-induced elevation of blood corticosterone, and (d) hindpaw-licking/biting responses induced by intraplantar injection of capsaicin. Among the NBPs and non-NBPs tested, only etidronate and clodronate displayed clear analgesic effects, with various routes of administration (including the oral one) being effective. However, they were ineffective when intraperitoneally injected simultaneously with acetic acid. Intracerebroventricular administration of etidronate or clodronate, but not of minodronate (an NBP), was also effective. The effective doses of etidronate and clodronate were much lower in writhing-high-responder strains of mice. Etidronate and clodronate reduced acetic acid-induced c-Fos expression in the brain and spinal cord, and also the acetic acid-induced corticosterone increase in the blood. Etidronate and clodronate each displayed an analgesic effect in the capsaicin test. Etidronate and clodronate displayed their analgesic effects at doses lower than those inducing anti-bone-resorptive effects. These results suggest that etidronate and clodronate exert potent, anti-bone-resorptive effect-independent analgesic effects, possibly via an interaction with neurons, and that they warrant reappraisal as safe drugs for osteoporosis.

Introduction

The bisphosphonates (BPs) (Fig. 1) bind strongly to bone hydroxyapatite, and the bone-bound BPs exert anti-bone-resorptive effects via their cytotoxic effects on osteoclasts (Rogers et al., 2000, Roelofs et al., 2006). Because nitrogen-containing bisphosphonates (NBPs) have greater anti-bone-resorptive effects than non-nitrogen-containing bisphosphonates (non-NBPs) (Fig. 1), NBPs are the current first-choice drugs for diseases involving enhanced bone resorption. However, attached to NBPs is the risk that they might cause osteonecrosis of jaws (Marx et al., 2005, Ruggiero et al., 2004, Ruggiero et al., 2009, Woo et al., 2006). Indeed, in Japan hundreds of cases of osteonecrosis of jaws have been reported, including patients treated with oral NBPs (Urade, 2010). It is noteworthy that in contrast, clear evidence is lacking that non-NBPs (e.g., etidronate and clodronate) cause such necrotic side effects. In fact, cases of osteonecrosis of jaws are very few among patients treated with these non-NBPs (Crépin et al., 2010), despite their coming into use much earlier than NBPs (e.g., etidronate was approved in 1977 in the USA and in 1990 in Japan).

Severe bone pain can result from bone metastases (Costa et al., 2006, Yoneda et al., 2011), and recent studies have led to NBPs being used against such metastatic pain (Costa et al., 2006, Von Moos et al., 2008). However, it should be noted that NBPs may cause painful trigeminal neuropathy via osteonecrosis of jaws (Zadik et al., 2012). Interestingly, Fujita et al. (2009) reported that in patients with osteoporosis and/or osteoarthritis, the analgesic effect of etidronate (a non-NBP) was greater than that of either alendronate or risedronate (both NBPs). In some animal studies (a) BPs have been shown to exhibit analgesic effects that are not associated with their anti-bone-resorptive effects (Goicoechea et al., 1999, Bonabell et al., 2001, Bonabello et al., 2003, Walker et al., 2002, Carvalho et al., 2006, Bianch et al., 2008, Kakimoto et al., 2008), and (b) clodronate (a non-NBP) has been found to have a more powerful analgesic effect than either pamidronate or alendronate (both NBPs) (Bonabell et al., 2001, Bonabello et al., 2003). However, those animal studies differed among themselves in animal species, experimental systems, BPs, routes of administration of BPs, and timing of BP administration, and the existing evidence is insufficient as regards comparisons of analgesic potencies among BPs, especially between NBPs and non-NBPs.

The writhing (abdominal constriction) response – induced in mice by intraperitoneally injecting dilute acetic acid – and the hindpaw-licking/biting response – induced in mice by intraplantar injection of capsaicin – are widely used for evaluating the analgesic effects of test materials (Koster et al., 1959, Vinegar et al., 1979, Sakurada et al., 2011). Here, using these methods, we compared the analgesic effects of various BPs used clinically against osteoporosis. We paid special attention to the effects of non-NBPs, especially etidronate, because it is the only non-NBP used clinically in Japan, and because little is known from animal experiments concerning such an anti-bone resorptive effect-independent analgesic effect of etidronate. In addition, we examined the effects of BPs on the two molecular markers for pain, c-Fos protein expression in neurons (Morgan and Curran, 1989) and the blood level of corticosterone (Yarushkina, 2008), which have not been examined in previous studies.

Section snippets

Mice

BALB/c mice were bred in our laboratory. C57BL/6, C3H/HeN, ICR, and ddY mice were purchased from SLC (Shizuoka, Japan). IL-1 knockout (IL-1-KO) mice (BALB/c background; deficient in both IL-1α and IL-1β), TNF-α KO mice (BALB/c background), and Triple-KO mice (TKO, BALB/c background; deficient in IL-1α, IL-1β, and TNF-α) were established from original IL-1α KO, IL-1β KO, and TNF-α KO mice (Horai et al., 1998, Tagawa et al., 1997). Histamine-H1-receptor (H1R) KO mice (C57BL/6 background) and

Evaluation of safe doses of non-NBPs

In the present study, in addition to etidronate and clodronate, we examined two other non-NBPs, oxidronate and medronate. Oxidronate and medronate are not used against osteoporosis but as carriers of 99mTc for bone scintigraphy. Before the experiments proper, we estimated the safe doses when the non-NBPs were given by various routes (Table 1). In all the following experiments, we used doses lower than those doses.

Effects of s.c.-injected etidronate and clodronate

We first examined the effects of s.c.-injected etidronate and clodronate (30 mg/kg)

Summary of the findings

The present findings may be summarized as follows. (i) Among the BPs tested, only etidronate and clodronate displayed clear analgesic effects, with various routes of administration being effective. (ii) In writhing-high-responder strains of mice, etidronate and clodronate were effective at much lower doses than in writhing-normal-responder strains. (iii) Etidronate and clodronate may exert their anti-bone-resorptive effect-independent analgesic effects via an interaction with neurons. (iv)

Conclusion

In mice, the non-NBPs etidronate and clodronate display potent anti-nociceptive or analgesic effects that are independent of their anti-bone-resorptive effects, possibly via an interaction with neurons. This encourages us to suggest the reappraisal of etidronate and clodronate as anti-osteoporosis drugs with a low risk of inflammatory and necrotic side effects.

Acknowledgments

This work was supported by grants from the Japan Society for the Promotion of Science (21390529, 20592318, and 21890019). We are grateful to Professor Koichi Tan-no (Department of Pharmacology, Tohoku Pharmaceutical University, Sendai, Japan) for teaching us the method used to remove spinal cords, to Professor Shinobu Sakurada (Department of Physiology and Anatomy, Tohoku Pharmaceutical University, Sendai, Japan) for teaching us the method used for the capsaicin test, and to Dr. Robert Timms

References (54)

  • T. Oizumi et al.

    Inhibition of necrotic actions of nitrogen-containing bisphosphonates (NBPs) and their elimination from bone by etidronate (a non-NBP): a proposal for possible utilization of etidronate as a substitution drug for NBPs

    J. Oral Maxillofac. Surg.

    (2010)
  • S.L. Ruggiero et al.

    Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases

    J. Oral Maxillofac. Surg.

    (2004)
  • S.L. Ruggiero et al.

    American association of oral maxillofacial surgeons position paper on bisphosphonate-related osteonecrosis of the jaw: 2009 update

    J. Oral Maxillofac. Surg.

    (2009)
  • T. Sakurada et al.

    Intraplantar injection of bergamot essential oil induces peripheral antinociception mediated by opioid mechanism

    Pharmacol. Biochem. Behav.

    (2011)
  • A. Sauty et al.

    Interleukin-6 and tumor necrosis factor α levels after bisphosphonates treatment in vitro and in patients with malignancy

    Bone

    (1996)
  • E. Siris

    Bisphosphonates and iritis

    Lancet

    (1993)
  • T. Sugimoto et al.

    c-fos induction in the subnucleus oralis following trigeminal nerve stimulation

    Brain Res.

    (1998)
  • K. Walker et al.

    Disease modifying and anti-nociceptive effects of the bisphosphonate, zoledronic acid in a model of bone cancer pain

    Pain

    (2002)
  • T. Yoneda et al.

    Involvement of acidic microenvironment in the pathophysiology of cancer-associated bone pain

    Bone

    (2011)
  • M. Zimmermann

    Ethical guidelines for investigations of experimental pain in conscious animals

    Pain

    (1983)
  • S. Adami et al.

    The acute-phase response after bisphosphonate administration

    Calcif. Tissue Int.

    (1987)
  • K. Amagase et al.

    Gastric ulcerogenic and healing impairment effects of risedronate, a nitrogen-containing bisphosphonate in rat. Comparison with alendronate and minodronate

    J. Physiol. Pharmacol.

    (2011)
  • S. Bang et al.

    Nociceptive and proinflammatory effects of dimethylallyl pyrophosphate via TRPV4 activation

    Br. J. Pharmacol.

    (2012)
  • M. Bianch et al.

    Effects of the bisphosphonate ibandronate on hyperalgesia, substance P, and cytokine levels in rat model

    Eur. J. Pain

    (2008)
  • O. Bock et al.

    Common musculoskeletal adverse effects of oral treatment with once weekly alendronate and risedronate in patients with osteoporosis and ways for their prevention

    J. Musculoskelet. Neuronal Interact.

    (2007)
  • A.P. Carvalho et al.

    Anti-inflammatory and anti-nociceptive activity of risedronate in experimental pain models in rat and mice

    Clin. Exp. Pharmacol. Physiol.

    (2006)
  • S. Crépin et al.

    Osteonecrosis of the jaw induced by clodronate, an alkylbisphosphonate: case report and literature review

    Eur. J. Clin. Pharmacol.

    (2010)
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