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