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

Oizumi, Takefumi; Funayama, Hiromi; Yamaguchi, Kouji; Yokoyama, Masayoshi; Takahashi, Harue; Yamamoto, Miou; Kuroishi, Toshinobu; Kumamoto, Hiroyuki; Sasaki, Keiichi; Kawamura, Hiroshi; Sugawara, Shunji; Endo, Yasuo

doi:10.1016/j.joms.2009.08.027

« Previous Next »Journal of Oral and Maxillofacial Surgery
Volume 68, Issue 5 , Pages 1043-1054, May 2010

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

Takefumi Oizumi, DDS
- Student, Department of Maxillofacial Surgery, Graduate School of Dentistry, Tohoku University, Sendai, Japan
Hiromi Funayama, DDS, PhD
- Assistant Professor, Department of Pediatric Dentistry, Tsurumi University, School of Dental Medicine, Yokohama, Japan
Kouji Yamaguchi, DDS, PhD
- Assistant Professor, Department of Maxillofacial Surgery, Graduate School of Dentistry, Tohoku University, Sendai, Japan
Masayoshi Yokoyama, DDS, PhD
- Assistant Professor, Department of Advanced Prosthetic Dentistry, Graduate School of Dentistry, Tohoku University, Sendai, Japan
Harue Takahashi, DDS
- Student, Department of Advanced Prosthetic Dentistry, Graduate School of Dentistry, Tohoku University, Sendai, Japan
Miou Yamamoto, DDS
- Student, Department of Advanced Prosthetic Dentistry, Graduate School of Dentistry, Tohoku University, Sendai, Japan
Toshinobu Kuroishi, PhD
- Assistant Professor, Department of Molecular Regulation, Graduate School of Dentistry, Tohoku University, Sendai, Japan
Hiroyuki Kumamoto, DDS, PhD
- Department of Oral Pathology, Graduate School of Dentistry, Tohoku University, Sendai, Japan
Keiichi Sasaki, DDS, PhD
- Professor, Department of Stomatognathic Physiology and Prosthodontics, Graduate School of Dentistry, Tohoku University, Sendai, Japan
Hiroshi Kawamura, DDS, PhD
- Professor, Department of Maxillofacial Surgery, Graduate School of Dentistry, Tohoku University, Sendai, Japan
Shunji Sugawara, DDS, PhD
- Professor, Department of Molecular Regulation, Graduate School of Dentistry, Tohoku University, Sendai, Japan
Yasuo Endo, PhD
- Associate Professor, Department of Molecular Regulation, Graduate School of Dentistry, Tohoku University, Sendai, Japan
- Address correspondence and reprint request to Dr Endo: Department of Molecular Regulation, Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan

published online 16 February 2010.

Purpose

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.

Materials and 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.