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.
OBJECTIVE
Nitrogen-containing bisphosphonates (NBPs) have powerful anti-bone-resorptive effects (ABREs). However, recent clinical applications have disclosed an unexpected side effect, osteonecrosis of the jaw. We previously found in mice that etidronate (a non-NBP), when coadministered with alendronate (an NBP), inhibited the latter's inflammatory effects. However, etidronate also reduced the ABRE of alendronate. The present study examined in mice the modulating effects of etidronate on the inflammatory and necrotic actions of zoledronate (the NBP with the strongest anti-bone-resorptive activity and the highest incidence of osteonecrosis of the jaw) and on ABREs of various NBPs including zoledronate.


METHODS
NBPs were subcutaneously injected into ear pinnas of mice and ensuing inflammation and necrosis at the site of the injection were evaluated. ABREs of NBPs were evaluated by analyzing sclerotic bands induced in mouse tibias.


RESULTS
Coinjection of etidronate reduced inflammatory and necrotic reactions induced by zoledronate, and also reduced the amount of zoledronate retained within the ear tissue. When both agents were intraperitoneally injected, etidronate reduced the ABRE of zoledronate and those of other NBPs. Notably, etidronate reduced the ABRE of zoledronate even when this non-NBP was injected 16 hours after the injection of zoledronate. Bone scintigram indicated that etidronate reduced the amount of zoledronate that had already bound to bone.


CONCLUSIONS
These results suggest that etidronate may 1) inhibit the entry of NBPs into cells related to inflammation and/or necrosis, 2) inhibit the binding of NBPs to bone hydroxyapatite, 3) at least partly eliminate (or substitute for) NBPs that have already accumulated within bones, and thus 4) if used as a substitution drug for NBPs, be effective at treating or preventing NBP-associated osteonecrosis of the jaw.
Department of Maxillofacial Surgery, Graduate School of Dentistry, Tohoku University, Sendai, Japan.
Takefumi
T
Oizumi
Hiromi
H
Funayama
Kouji
K
Yamaguchi
Masayoshi
M
Yokoyama
Harue
H
Takahashi
Miou
M
Yamamoto
Toshinobu
T
Kuroishi
Hiroyuki
H
Kumamoto
Keiichi
K
Sasaki
Hiroshi
H
Kawamura
Shunji
S
Sugawara
Yasuo
Y
Endo
D019386:Alendronate / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D000818:Animals; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D001862:Bone Resorption / Q000503:physiopathology / Q000517:prevention & control; D004164:Diphosphonates / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D004431:Ear, External / Q000187:drug effects / Q000473:pathology; D012968:Etidronic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005260:Female; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D007093:Imidazoles / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D007375:Interleukin-1 / Q000172:deficiency; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009336:Necrosis; D010020:Osteonecrosis / Q000139:chemically induced / Q000503:physiopathology; D010026:Osteosclerosis / Q000139:chemically induced / Q000517:prevention & control; D000077268:Pamidronate; D017035:Pravastatin / Q000008:administration & dosage / Q000494:pharmacology; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals; D000068296:Risedronic Acid; D013667:Technetium; D013977:Tibia / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D013997:Time Factors; D000077211:Zoledronic Acid
D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007093:Imidazoles; D018836:Inflammation Mediators; D007375:Interleukin-1; D019275:Radiopharmaceuticals; D000077211:Zoledronic Acid; D013667:Technetium; D000068296:Risedronic Acid; D017035:Pravastatin; D012968:Etidronic Acid; D000077268:Pamidronate; D019386:Alendronate