Necrotic actions of nitrogen-containing bisphosphonates and their inhibition by clodronate, a non-nitrogen-containing bisphosphonate in mice: potential for utilization of clodronate as a combination drug with a nitrogen-containing bisphosphonate.
Nitrogen-containing bisphosphonates (NBPs) exhibit powerful anti-bone-resorptive effects (ABREs) via inhibition of farnesyl pyrophosphate synthase during cholesterol biosynthesis. Clinical applications have disclosed an unexpected side effect, namely osteonecrosis of jaw bones, and although thousands of cases have been documented in the last few years the mechanism remains unclear. Since NBPs accumulate in bone-hydroxyapatite, more jaw bone osteonecrosis cases may come to light if NBPs continue to be used as they are being used now. We have previously reported that in mice, systemic (intraperitoneal) injection of clodronate (a non-NBP) prevents the inflammatory effects of NBPs. Here, we examined in mice the local necrotic actions of various NBPs and the anti-necrotic effects of clodronate. A single subcutaneous injection of an NBP into the ear pinna induced necrosis at the injection site (relative potencies of necrotic actions of NBPs: zoledronate >> pamidronate > or = alendronate > risedronate), while non-NBPs lacked this effect. Clodronate, when injected together with an NBP, reduced or prevented the necrosis induced by that NBP, but not its ABRE. Clodronate reduced the amount of each NBP retained within tissues. These results, together with those of previous studies, suggest that (i) clodronate inhibits the inflammatory and necrotic actions of NBPs by inhibiting their incorporation into cells related to inflammation and/or necrosis, (ii) clodronate could be useful as a combination drug with NBPs for preventing their necrotic actions while retaining their ABREs and (iii) clodronate could also be useful as a substitution drug for NBPs in patients at risk of osteonecrosis of jaw bones.
Department of Molecular Regulation, Graduate School of Dentistry, Tohoku University, Seiryo-machi, Aoba-ku, Sendai, Japan.
Takefumi
T
Oizumi
Kouji
K
Yamaguchi
Hiromi
H
Funayama
Toshinobu
T
Kuroishi
Hiroshi
H
Kawamura
Shunji
S
Sugawara
Yasuo
Y
Endo
D000818:Animals; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000737:chemistry / Q000494:pharmacology; D004002:Clodronic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D004164:Diphosphonates / Q000008:administration & dosage / Q000009:adverse effects* / Q000737:chemistry / Q000494:pharmacology; D004338:Drug Combinations; D003875:Drug Eruptions / Q000209:etiology / Q000517:prevention & control; D005260:Female; D007274:Injections, Intraperitoneal; D051379:Mice; D008807:Mice, Inbred BALB C; D009584:Nitrogen / Q000737:chemistry*; D010020:Osteonecrosis / Q000139:chemically induced / Q000517:prevention & control*; D012867:Skin / Q000187:drug effects / Q000473:pathology; D013329:Structure-Activity Relationship
D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D004338:Drug Combinations; D004002:Clodronic Acid; D009584:Nitrogen