Zoledronic acid delays wound healing of the tooth extraction socket, inhibits oral epithelial cell migration, and promotes proliferation and adhesion to hydroxyapatite of oral bacteria, without causing osteonecrosis of the jaw, in mice

• Published in: Journal of bone and mineral metabolism Vol. 28; no. 2; pp. 165 - 175
• Main Authors: Kobayashi, Yasuyoshi, Hiraga, Toru, Ueda, Akimi, Wang, Liyang, Matsumoto-Nakano, Michiyo, Hata, Kenji, Yatani, Hirofumi, Yoneda, Toshiyuki
• Format: Journal Article
• Language: English
• Published: Japan Springer Japan 01-03-2010; Springer; Springer Nature B.V
• Subjects: Angiogenesis; Animals; Bacterial Adhesion - drug effects; Bacterial Physiological Phenomena - drug effects; Biological and medical sciences; Bone Density Conservation Agents - administration & dosage; Bone Density Conservation Agents - adverse effects; Bone Density Conservation Agents - chemistry; Bone Density Conservation Agents - pharmacology; Cell Movement - drug effects; Cell physiology; Cell Proliferation - drug effects; Cells, Cultured; Dental Plaque - microbiology; Diphosphonates - administration & dosage; Diphosphonates - adverse effects; Diphosphonates - chemistry; Diphosphonates - pharmacology; Diseases of the osteoarticular system; Dose-Response Relationship, Drug; Female; Fundamental and applied biological sciences. Psychology; Humans; Hydroxyapatite; Imidazoles - administration & dosage; Imidazoles - adverse effects; Imidazoles - chemistry; Imidazoles - pharmacology; Jaw Diseases - physiopathology; Jaw Diseases - prevention & control; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Mice; Mice, Inbred Strains; Mineralization, calcification; Molecular and cellular biology; Mouth Mucosa - drug effects; Mouth Mucosa - microbiology; Neovascularization, Physiologic - drug effects; Original Article; Orthopedics; Osteogenesis - drug effects; Osteonecrosis - physiopathology; Osteonecrosis - prevention & control; Pathogenesis; Skeleton and joints; Streptococcus mutans - drug effects; Streptococcus mutans - metabolism; Tooth Extraction; Tooth Socket - pathology; Tooth Socket - physiology; Vascular bone diseases; Vertebrates: osteoarticular system, musculoskeletal system; Wound healing; Wound Healing - drug effects; Angiogenesis; Osteoclasts; Bacterial adhesion; Osteogenesis; Cell proliferation; Jaw; Antiosteoporotic; Migration; Diseases of the osteoarticular system; Hydroxyapatite; Osteoclast; Osteonecrosis; Wound; Zoledronic acid; Bacteria; Extraction; Cicatrization; Rodentia; Rheumatology; Oral administration; Infection; Vertebrata; Mammalia; Mouse; Animal; Bacteriosis; Epithelial cell; Tooth
• ISSN: 0914-8779; 1435-5604
• DOI: 10.1007/s00774-009-0128-9

Nitrogen-containing bisphosphonates such as zoledronic acid (ZOL) and pamidronate have been widely and successfully used for the treatment of cancer patients with bone metastases and/or hypercalcemia. Accumulating recent reports have shown that cancer patients who have received these bisphosphonates occasionally manifest bisphosphonate-related osteonecrosis of the jaw (BRONJ) following dental treatments, including tooth extraction. However, little is known about the pathogenesis of BRONJ to date. Here, to understand the underlying pathogenesis of BRONJ, we examined the effects of ZOL on wound healing of the tooth extraction socket using a mouse tooth extraction model. Histomorphometrical analysis revealed that the amount of new bone and the numbers of blood vessels in the socket were significantly decreased in ZOL-treated mice compared to control mice. Consistent with these results, ZOL significantly inhibited angiogenesis induced by vascular endothelial growth factor in vivo and the proliferation of endothelial cells in culture in a dose-dependent manner. In contrast, etidronate, a non-nitrogen-containing bisphosphonate, showed no effects on osteogenesis and angiogenesis in the socket. ZOL also suppressed the migration of oral epithelial cells, which is a crucial step for tooth socket closure. In addition, ZOL promoted the adherence of
Streptococcus mutans
to hydroxyapatite and the proliferation of oral bacteria obtained from healthy individuals, suggesting that ZOL may increase the bacterial infection. In conclusion, our data suggest that ZOL delays wound healing of the tooth extraction socket by inhibiting osteogenesis and angiogenesis. Our data also suggest that ZOL alters oral bacterial behaviors. These actions of ZOL may be relevant to the pathogenesis of BRONJ.