title: Analysis of the time-to-onset of osteonecrosis of jaw with bisphosphonate treatment using the data from a spontaneous reporting system of adverse drug events.
abstract: BACKGROUND
  Bisphosphonates (BPs) are potent antiresorptive agents used to treat osteoporosis and the complications associated with malignant bone metastasis. The aim of this study was to evaluate the incidence of bisphosphonate-related osteonecrosis of the jaw (BRONJ) using the Japanese Adverse Drug Event Report (JADER) database. In particular, we focused on the time-to-onset profile of BRONJ.
  
  
  RESULTS
  We analyzed reports of BRONJ in the JADER database and calculated the reporting odds ratio (ROR) of BPs potentially associated with BRONJ. We applied the weibull shape parameter to time-to-event data in JADER. The drugs selected for this investigation were seven BPs approved in Japan (alendronate [intraveneous, I.V.], pamidronate, and zoledronate as I.V. BPs; and alendronate (oral), etidronate, minodronate, and risedronate as oral BPs). We analyzed reports of BRONJ events associated with BPs in the JADER database from April 2004 to November 2014. The median value of BRONJ cases caused by alendronate (I.V.), pamidronate, zoledronate, alendronate (oral), etidronate, minodronate, and risedronate were 1342, 812, 486, 863, 1461, 432, and 730 days, respectively. The lower 95 % confidence interval of the Weibull-shape parameter β for I.V. BPs (pamidronate and zoledronate) exceeded 1. The risk of BRONJ with I.V. BPs increased over time.
  
  
  CONCLUSIONS
  Thus, the incidence of BRONJ with BP treatment should be closely monitored for a 3-year period. Further studies are required to draw conclusions, and we believe that this information about BRONJ induced by BPs will prove beneficial to patients and pharmacists.
authors.affiliation: Laboratory of Drug Informatics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196 Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Laboratory of Drug Informatics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196 Japan ; Present address: Clinical Research, Innovation and Education Center, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba Ward, Sendai, Miyagi 980-8574 Japan.
authors.forename: Ryogo
authors.initials: R
authors.lastname: Umetsu
authors.affiliation: Laboratory of Drug Informatics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196 Japan ; Medical Database Co., LTD, 3-11-10 Higashi, Shibuya-ku, Tokyo 150-0011 Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Abe
authors.affiliation: Laboratory of Drug Informatics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196 Japan.
authors.forename: Toshinobu
authors.initials: T
authors.lastname: Matsui
authors.affiliation: Laboratory of Drug Informatics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196 Japan.
authors.forename: Natsumi
authors.initials: N
authors.lastname: Ueda
authors.affiliation: Laboratory of Drug Informatics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196 Japan.
authors.forename: Yamato
authors.initials: Y
authors.lastname: Kato
authors.affiliation: Laboratory of Drug Informatics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196 Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Sasaoka
authors.affiliation: Laboratory of Pharmaceutical Engineering, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196 Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Tahara
authors.affiliation: Laboratory of Pharmaceutical Engineering, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196 Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Takeuchi
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu, 501-1194 Japan.
authors.forename: Yasutomi
authors.initials: Y
authors.lastname: Kinosada
keywords: Bisphosphonate; Japanese adverse drug event report database; Osteonecrosis of jaw
references.citation: Pharmacoepidemiol Drug Saf. 2002 Jan-Feb;11(1):3-10
references.pmid: 11998548
references.citation: Proc Natl Acad Sci U S A. 2006 May 16;103(20):7829-34
references.pmid: 16684881
references.citation: J Dent Educ. 2008 Aug;72(8):919-29
references.pmid: 18676801
references.citation: J Oral Maxillofac Surg. 2010 Feb;68(2):243-53
references.pmid: 19772941
references.citation: Aust Endod J. 2009 Dec;35(3):119-30
references.pmid: 19961450
references.citation: J Bone Miner Metab. 2010 Jul;28(4):365-83
references.pmid: 20333419
references.citation: Drug Healthc Patient Saf. 2010;2:121-37
references.pmid: 21701624
references.citation: J Oral Maxillofac Surg. 2011 Nov;69(11):e364-71
references.pmid: 21782307
references.citation: Ann Oncol. 2012 May;23(5):1341-7
references.pmid: 21986094
references.citation: Clin Cases Miner Bone Metab. 2007 Jan;4(1):37-42
references.pmid: 22460751
references.citation: Drug Saf. 2012 Jul 1;35(7):599-610
references.pmid: 22702641
references.citation: Drug Saf. 2013 Oct;36(10):995-1006
references.pmid: 23673816
references.citation: Ther Adv Musculoskelet Dis. 2013 Aug;5(4):182-98
references.pmid: 23904863
references.citation: Yakugaku Zasshi. 2014;134(2):299-304
references.pmid: 24492232
references.citation: J Oral Maxillofac Surg. 2014 Oct;72(10):1938-56
references.pmid: 25234529
references.citation: Biol Pharm Bull. 2015;38(5):680-6
references.pmid: 25947914
references.citation: J Pharm Health Care Sci. 2015 Apr 16;1:15
references.pmid: 26819726