Bisphosphonate 休薬期間が抜歯窩治癒過程に及ぼす影響についての実験的研究
The use of bisphosphonate (BP) after dental extraction has been reported to cause bisphosphonate-related osteonecrosis of the jaw (BRONJ). Avoidance of oral BP is recommended; however, no guidelines exist for intravenous BP. Therefore, we evaluated the influence of intravenous BP drug holiday (BPdh)...
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| Published in | 日本口腔外科学会雑誌 Vol. 60; no. 11; pp. 596 - 608 |
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| Main Authors | , , , , , , , |
| Format | Journal Article |
| Language | Japanese |
| Published |
社団法人 日本口腔外科学会
20.11.2014
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| Subjects | |
| Online Access | Get full text |
| ISSN | 0021-5163 2186-1579 |
| DOI | 10.5794/jjoms.60.596 |
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| Abstract | The use of bisphosphonate (BP) after dental extraction has been reported to cause bisphosphonate-related osteonecrosis of the jaw (BRONJ). Avoidance of oral BP is recommended; however, no guidelines exist for intravenous BP. Therefore, we evaluated the influence of intravenous BP drug holiday (BPdh) on post-extraction healing. Japanese white rabbits were used. In the sham group, saline was administered intravenously, and the mandibular premolar teeth were extracted; then, the mandible was collected 2-10 weeks after teeth extraction. In the BPdh group, zoledronate was administered intravenously. After 0, 1, 3, and 6 weeks of BPdh, the teeth were extracted. The jaws were collected 6 weeks after the tooth extractions. The healing status of the extraction socket was assessed. The cancellous bone volume (BV/ TV), trabecular separation (Tb. Sp), and trabecular number (Tb. N) of the mandibular bone lingual side were measured with microfocus X-ray images as healing index. In the sham group, bone exposure was not observed; BV/ TV 2-10 weeks after tooth extraction decreased from 54.04% to 12.30%; Tb.N decreased from 3.02/mm to 0.83/mm; Tb. Sp increased from 75.10μm to 285.31μm; and bone remodeling on cancellous bone increased at 6 weeks. The results in the sham group at post-extraction 6 weeks, serving as control, were compared with those in the BPdh group. In the BPdh group, bone was temporarily visible (BRONJ Stage 1) in the 0-3 week groups. Tb.N and BV/ TV in all of the 0-6 week groups were significantly higher than those in the control group; these values were significantly lower in the 6 week group than in the 0 week group. Tb. Sp was significantly higher in the 6 week group than in the 0 week group, but the value was significantly lower in both groups than in the control group. BP administration resulted in changes in BV/ TV, Tb. N, and Tb. Sp and a delay in the healing process at the extraction site. A possible mechanism might be as follows:(1) BP accumulates in the jaws and is incorporated into osteoclasts; (2) after apoptosis of osteoclasts, BP may reattach to the surface of new trabecular bone in the extraction wound even during BPdh. The cancellous bone in the 6-week BPdh group was closer to that in the control group than that in the 0 week BPdh group. Healing following tooth extraction in patients who receive intravenous BP therapy may be promoted by BPdh. |
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| AbstractList | The use of bisphosphonate (BP) after dental extraction has been reported to cause bisphosphonate-related osteonecrosis of the jaw (BRONJ). Avoidance of oral BP is recommended; however, no guidelines exist for intravenous BP. Therefore, we evaluated the influence of intravenous BP drug holiday (BPdh) on post-extraction healing. Japanese white rabbits were used. In the sham group, saline was administered intravenously, and the mandibular premolar teeth were extracted; then, the mandible was collected 2-10 weeks after teeth extraction. In the BPdh group, zoledronate was administered intravenously. After 0, 1, 3, and 6 weeks of BPdh, the teeth were extracted. The jaws were collected 6 weeks after the tooth extractions. The healing status of the extraction socket was assessed. The cancellous bone volume (BV/ TV), trabecular separation (Tb. Sp), and trabecular number (Tb. N) of the mandibular bone lingual side were measured with microfocus X-ray images as healing index. In the sham group, bone exposure was not observed; BV/ TV 2-10 weeks after tooth extraction decreased from 54.04% to 12.30%; Tb.N decreased from 3.02/mm to 0.83/mm; Tb. Sp increased from 75.10μm to 285.31μm; and bone remodeling on cancellous bone increased at 6 weeks. The results in the sham group at post-extraction 6 weeks, serving as control, were compared with those in the BPdh group. In the BPdh group, bone was temporarily visible (BRONJ Stage 1) in the 0-3 week groups. Tb.N and BV/ TV in all of the 0-6 week groups were significantly higher than those in the control group; these values were significantly lower in the 6 week group than in the 0 week group. Tb. Sp was significantly higher in the 6 week group than in the 0 week group, but the value was significantly lower in both groups than in the control group. BP administration resulted in changes in BV/ TV, Tb. N, and Tb. Sp and a delay in the healing process at the extraction site. A possible mechanism might be as follows:(1) BP accumulates in the jaws and is incorporated into osteoclasts; (2) after apoptosis of osteoclasts, BP may reattach to the surface of new trabecular bone in the extraction wound even during BPdh. The cancellous bone in the 6-week BPdh group was closer to that in the control group than that in the 0 week BPdh group. Healing following tooth extraction in patients who receive intravenous BP therapy may be promoted by BPdh. |
| Author | 細原, 政俊 江㞍, 貞一 渡邉, 竜太 村木, 智則 伊藤, 友里 式守, 道夫 厚地, 功誠 笠井, 唯克 |
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| References | 1) Rogers MJ, Frith JC, et al : Molecular mechanisms of action of bisphosphonates. Bone 24: 73S-79S, 1999. 9) Kobayashi Y, Hiraga T, et al : 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. J Bone Miner Metab 28: 165-175, 2009. 7) 浦出雅裕：ビスフォスフォネート治療による顎骨壊死発症の現状. 日口外誌 56: 292-297, 2010. 13) Ruggiero SL, Dodson TB, et al : American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws- 2009 update. J Oral Maxillofac Surg 67: 2-12, 2009. 26) Hughes DE, Wright KR, et al : Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo. J Bone Miner Res 10: 1478-1487, 1995. 32) Ito M, Amizuka N, et al : Ultrastructural and cytochemical studies on cell death of osteoclasts induced by bisphosphonate treatment. Bone 25: 447-452, 1999. 3) 伊東昌子：ビスホスホネート治療の新展開 ビスホスホネート治療の骨構造特性への影響. Clinical Calcium 19: 20-29, 2009. 19) 小澤英浩, 中村浩彰：骨の組織学的構造の特徴. 須田立雄, 小澤英浩, 他編著；新 骨の科学. 第1版, 医歯薬出版, 東京, 2007, 24-26頁. 31) Chapurlat RD and Delmas PD: Drug insight: Bisphosphonates for postmenopausal osteoporosis. Nat Clin Pract Endocrinol Metab 2: 211-219, 2006. 27) 小澤英浩, 網塚憲生：硬組織細胞とアポトーシス 骨組織におけるアポトーシス. THE BONE 13: 47-56, 1999. 4) Marx RE: Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 61: 1115-1117, 2003. 18) Kawada K, Minami H, et al : A multicenter and open label clinical trial of zoledronic acid 4 mg in patients with hypercalcemia of malignancy. Jpn J Clin Oncol 35: 28-33, 2005. 21) Rodan GA and Fleisch HA: Bisphosphonates: mechanisms of action. J Clin Invest 97: 2692-2696, 1996. 2) Licata AA: Discovery, clinical developmemt, and therapeutic uses of bisphosphonates. Ann Pharma Cothear 39: 668-677, 2005. 16) Magopoulos C, Karakinaris G, et al : Osteonecrosis of the jaws due to bisphosphonate use. A review of 60 cases and treatment proposals. Am J Otolaryngol 28: 158-163, 2007. 24) Migliorati CA, Casiglia J, et al : Managing the care of patients with bisphosphonate-associated osteonecrosis: an American Academy of Oral Medicine position paper. J Am Dent Assoc 13: 1658-1668, 2005. 23) Santini D, Vincenzi B, et al : Zoledronic acid induces significant and long-lasting modification of circulating angiogenic factor in cancer patients. Clin Cancer Res 9: 2893-2897, 2003. 28) 真柴 賛, 森 諭史：骨質評価法としての骨石灰化度測定－イヌ肋骨皮質骨における解析. Osteoporos Jpn 12: 529-533, 2004. 29) Mashiba T, Mori S, et al : The effects of suppressed bone remodeling by bisphosphonates on microdamage accumulation and degree of mineralization in the cortical bone of dog rib. J Bone Miner Metab 23: 36-42, 2005. 5) Yoneda T, Hagino H, et al : Bisphosphonate-related osteonecrosis of the jaw: position paper from the Allied Task Force Committee of Japanese Society for Bone and Mineral Research, Japan Osteoporosis Society, Japanese Society of Periodontology, Japanese Society for Oral and Maxillofacial Radiology, and Japanese Society of Oral and Maxillofacial Surgeons. J Bone Miner Metab 28: 365-383, 2010. 11) 室井悠里, 中嶋正博, 他：経口ビスフォスフォネート製剤患者の抜歯創治癒経過に関する臨床的検討. 日口外誌 57: 452-458, 2011. 25) 小澤英浩, 中村浩彰, 他：骨質骨の微細構造と骨質 (1). THE BONE 21: 21-34, 2007. 15) Stanton DC and Balasanian E : Outcome of surgical management of bisphosphonate-related osteonecrosis of the jaws: review of 33 surgical cases. J Oral Maxillofac Surg 67: 943-950, 2009. 17) 伊藤 隆, 白石一成：ウサギの冠状動脈および大動脈の灌流固定法. 日本実験動物技術者協会 図解・ 実験動物技術集編集委員会編；図解・実験動物技術集I. 増訂第4版, 株式会社アドスリー, 東京, 2005, 141-142頁. 33) Ito M, Amizuka N, et al : Bisphosphonate acts on osteoclasts independent of ruffled borders in osteosclerotic (oc/ oc) mice. Bone 28: 609-616, 2001. 8) 佐伯典彦, 飯塚 正, 他：ラット抜歯創治癒過程におよぼすBisphosphonateの全身ならびに局所投与による影響について. 北海道歯誌 22: 185-201, 2001. 6) 米田俊之，萩野 浩, 他：ビスフォスフォネート関連顎骨壊死に対するポジションペーパー (改訂追補2012年度). Available at : jsbmr.umin.jp/pdf/BRONJpositionpaper2012.pdf. Accessed october 23, 2013. 12) 伊藤友里, 厚地功誠, 他：ビスフォスフォネート製剤投与患者の臨床的検討. 岐歯学誌40: 119-126, 2013. 22) Landesberg R, Woo V, et al : Potential pathophysiological mechanisms in osteonecrosis of the jaw. Ann NY Acad Sci 1218: 62-79, 2011. 30) Weiss HM, Pfaar U, et al : Biodistribution and plasma protein binding of zoledronic acid. Drug Metab Dispos 36: 2043-2049, 2008. 10) Hikita H, Miyazawa K, et al : Bisphoshonate administration prior to tooth extraction delays initial healing of the extraction socet in rats. J Bone Miner Metab 27: 663-672, 2009. 14) Wilde F, Heufelder M, et al : The role of surgical therapy in the management of intravenous bisphosphonates-related osteonecrosis of the jaw. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 111: 153-163, 2011. 20) 大竹隆之, 桜井富士朗：ウサギの医・食・住．初版, どうぶつ出版, 東京, 2000, 174頁. |
| References_xml | – reference: 7) 浦出雅裕：ビスフォスフォネート治療による顎骨壊死発症の現状. 日口外誌 56: 292-297, 2010. – reference: 8) 佐伯典彦, 飯塚 正, 他：ラット抜歯創治癒過程におよぼすBisphosphonateの全身ならびに局所投与による影響について. 北海道歯誌 22: 185-201, 2001. – reference: 4) Marx RE: Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 61: 1115-1117, 2003. – reference: 10) Hikita H, Miyazawa K, et al : Bisphoshonate administration prior to tooth extraction delays initial healing of the extraction socet in rats. J Bone Miner Metab 27: 663-672, 2009. – reference: 18) Kawada K, Minami H, et al : A multicenter and open label clinical trial of zoledronic acid 4 mg in patients with hypercalcemia of malignancy. Jpn J Clin Oncol 35: 28-33, 2005. – reference: 17) 伊藤 隆, 白石一成：ウサギの冠状動脈および大動脈の灌流固定法. 日本実験動物技術者協会 図解・ 実験動物技術集編集委員会編；図解・実験動物技術集I. 増訂第4版, 株式会社アドスリー, 東京, 2005, 141-142頁. – reference: 5) Yoneda T, Hagino H, et al : Bisphosphonate-related osteonecrosis of the jaw: position paper from the Allied Task Force Committee of Japanese Society for Bone and Mineral Research, Japan Osteoporosis Society, Japanese Society of Periodontology, Japanese Society for Oral and Maxillofacial Radiology, and Japanese Society of Oral and Maxillofacial Surgeons. J Bone Miner Metab 28: 365-383, 2010. – reference: 12) 伊藤友里, 厚地功誠, 他：ビスフォスフォネート製剤投与患者の臨床的検討. 岐歯学誌40: 119-126, 2013. – reference: 22) Landesberg R, Woo V, et al : Potential pathophysiological mechanisms in osteonecrosis of the jaw. Ann NY Acad Sci 1218: 62-79, 2011. – reference: 13) Ruggiero SL, Dodson TB, et al : American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws- 2009 update. J Oral Maxillofac Surg 67: 2-12, 2009. – reference: 21) Rodan GA and Fleisch HA: Bisphosphonates: mechanisms of action. J Clin Invest 97: 2692-2696, 1996. – reference: 25) 小澤英浩, 中村浩彰, 他：骨質骨の微細構造と骨質 (1). THE BONE 21: 21-34, 2007. – reference: 29) Mashiba T, Mori S, et al : The effects of suppressed bone remodeling by bisphosphonates on microdamage accumulation and degree of mineralization in the cortical bone of dog rib. J Bone Miner Metab 23: 36-42, 2005. – reference: 15) Stanton DC and Balasanian E : Outcome of surgical management of bisphosphonate-related osteonecrosis of the jaws: review of 33 surgical cases. J Oral Maxillofac Surg 67: 943-950, 2009. – reference: 1) Rogers MJ, Frith JC, et al : Molecular mechanisms of action of bisphosphonates. Bone 24: 73S-79S, 1999. – reference: 6) 米田俊之，萩野 浩, 他：ビスフォスフォネート関連顎骨壊死に対するポジションペーパー (改訂追補2012年度). Available at : jsbmr.umin.jp/pdf/BRONJpositionpaper2012.pdf. Accessed october 23, 2013. – reference: 24) Migliorati CA, Casiglia J, et al : Managing the care of patients with bisphosphonate-associated osteonecrosis: an American Academy of Oral Medicine position paper. J Am Dent Assoc 13: 1658-1668, 2005. – reference: 9) Kobayashi Y, Hiraga T, et al : 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. J Bone Miner Metab 28: 165-175, 2009. – reference: 11) 室井悠里, 中嶋正博, 他：経口ビスフォスフォネート製剤患者の抜歯創治癒経過に関する臨床的検討. 日口外誌 57: 452-458, 2011. – reference: 23) Santini D, Vincenzi B, et al : Zoledronic acid induces significant and long-lasting modification of circulating angiogenic factor in cancer patients. Clin Cancer Res 9: 2893-2897, 2003. – reference: 19) 小澤英浩, 中村浩彰：骨の組織学的構造の特徴. 須田立雄, 小澤英浩, 他編著；新 骨の科学. 第1版, 医歯薬出版, 東京, 2007, 24-26頁. – reference: 26) Hughes DE, Wright KR, et al : Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo. J Bone Miner Res 10: 1478-1487, 1995. – reference: 28) 真柴 賛, 森 諭史：骨質評価法としての骨石灰化度測定－イヌ肋骨皮質骨における解析. Osteoporos Jpn 12: 529-533, 2004. – reference: 33) Ito M, Amizuka N, et al : Bisphosphonate acts on osteoclasts independent of ruffled borders in osteosclerotic (oc/ oc) mice. Bone 28: 609-616, 2001. – reference: 14) Wilde F, Heufelder M, et al : The role of surgical therapy in the management of intravenous bisphosphonates-related osteonecrosis of the jaw. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 111: 153-163, 2011. – reference: 32) Ito M, Amizuka N, et al : Ultrastructural and cytochemical studies on cell death of osteoclasts induced by bisphosphonate treatment. Bone 25: 447-452, 1999. – reference: 27) 小澤英浩, 網塚憲生：硬組織細胞とアポトーシス 骨組織におけるアポトーシス. THE BONE 13: 47-56, 1999. – reference: 3) 伊東昌子：ビスホスホネート治療の新展開 ビスホスホネート治療の骨構造特性への影響. Clinical Calcium 19: 20-29, 2009. – reference: 2) Licata AA: Discovery, clinical developmemt, and therapeutic uses of bisphosphonates. Ann Pharma Cothear 39: 668-677, 2005. – reference: 20) 大竹隆之, 桜井富士朗：ウサギの医・食・住．初版, どうぶつ出版, 東京, 2000, 174頁. – reference: 30) Weiss HM, Pfaar U, et al : Biodistribution and plasma protein binding of zoledronic acid. Drug Metab Dispos 36: 2043-2049, 2008. – reference: 16) Magopoulos C, Karakinaris G, et al : Osteonecrosis of the jaws due to bisphosphonate use. A review of 60 cases and treatment proposals. Am J Otolaryngol 28: 158-163, 2007. – reference: 31) Chapurlat RD and Delmas PD: Drug insight: Bisphosphonates for postmenopausal osteoporosis. Nat Clin Pract Endocrinol Metab 2: 211-219, 2006. |
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| SubjectTerms | micro-CT 休薬期間 家兎 抜歯窩治癒 顎骨壊死 |
| Title | Bisphosphonate 休薬期間が抜歯窩治癒過程に及ぼす影響についての実験的研究 |
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| ispartofPNX | 日本口腔外科学会雑誌, 2014/11/20, Vol.60(11), pp.596-608 |
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