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

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.