Osteonecrosis of the jaw induced by clodronate, an alkylbiphosphonate: case report and literature review

Abstract

Purpose To report on a case of osteonecrosis of the jaw (ONJ) in a patient treated with clodronate, an alkylbiphosphonate, and to draw attention to the risk of ONJ following treatment with all biphosphonates, whether they are alkyl-or amino-biphosphonates. Case report Beginning at age 58 years, a female patient took clodronate for almost 13 years for a metastatic bone cancer. She also underwent chemotherapy and radiotherapy. Three months after the end of biphosphonate therapy, she suffered from toothache, and tooth 27 (left maxillary second molar) was extracted. A maxillary focus of osteitis with an oral sinus communication was discovered, and a maxillofacial denture prosthesis was grafted in September 2006. Some days later, the patient consulted her dentist for an ulceration of the oral cavity floor in front of tooth 33 (left mandibular canine) extending to the left inferior side of the lip. In October 2006, teeth 33 and 34 (left mandibular first premolar) were extracted. No secondary infection occurred. A complete healing was only observed 3 months after the last extraction. ONJ due to alkylbiphosphonate treatment was diagnosed as bone reconstruction and mucous cicatrisation were delayed. Methods A systematic review was carried out to identify all cases of alkylbiphosphonate-induced ONJ by searching the Medline and Cochrane databases using 'osteonecrosis of the jaw', 'jaw diseases', 'osteonecrosis', 'diphosphonate', 'biphosphonate' (amino-, alkyl-or the international nonproprietary name) as the main search items. The search was limited to English-and French-language articles published between 1966 and February 2010. Results Our search identified 27 cases of alkylbiphosphonateinduced ONJ in the literature. Among these cases, only ten patients were on alkylbiphosphonate monotherapy; in the other cases, aminobiphosphonates had also been used. The clinical presentation of the alkylbiphosphonate-induced ONJ was similar to that most often encountered with aminobiphosphonate treatment. The duration of exposure before onset was higher with alkylbiphosphonates than with aminobiphosphonates, and dental procedures before ONJ were frequent. Conclusion Osteonecrosis of the jaw has been widely reported with various aminobiphosphonates, but data on the role of alkylbiphosphonates are scarce. As these latter drugs are less potent, a high cumulative dose through long-term exposure would appear to be necessary and would favour ONJ. Although the degree of risk for ONJ occurrence in patients on alkylbiphosphonates remains uncertain, it would be wise to reconsider carefully the indications for using these agents and to apply preventive measures as is currently done for aminobiphosphonates.

Inflammatory Effects of Nitrogen-Containing Bisphosphonates (N-BPs): Modulation by Non-N-BPs

“…Possible Clinical Applications of Eti, Clo, and Til There are only a few reports of inflammatory/necrotic side effects occurring in patients treated with either Eti or Clo, 33) and there is no clinical report of Til-associated inflammatory or necrotic side effects. Of the BPs shown in Table 3, the antibone-resorptive effect of Eti is the smallest.…”

A Strategy against the Osteonecrosis of the Jaw Associated with Nitrogen-Containing Bisphosphonates (N-BPs): Attempts to Replace N-BPs with the Non-N-BP Etidronate

“…10) Indeed, the non-N-BPs etidronate and clodronate almost completely lack inflammatory and necrotic effects in mice, 7,16) and they are hardly retained at all within soft-tissues in mice after intravenous injection. 17) On the contrary, they antagonize the entry of N-BPs into softtissues.…”

“…Interestingly and importantly, few BRONJ cases have been reported in patients treated with the non-N-BP etidronate. 10) We previously reported that in mice: (i) etidronate, when coadministered with, or administered after, an N-BP, competes with the N-BP for binding to bone hydroxyapatite, 7,11) and (ii) etidronate can reduce the inflammatory and necrotic effects of N-BPs [7][8][9][10][11] by inhibiting their entry into soft-tissue cells.…”

Inflammatory and Necrotic Effects of Minodronate, a Nitrogen-Containing Bisphosphonate, in Mice

“…ONJ cases are very scarce in patients treated with non-N-BPs (clodronate and etidronate) (Crépin et al 2010), although it is not clear whether these non-N-BPs have any INSEs, such as those of N-BPs. Concerning the INSEs of N-BPs in mice, we have reported that clodronate and etidronate can reduce or prevent the systemic and local INSEs of various N-BPs (Endo et al 1999;Funayama et al 2005;Oizumi et al 2009Oizumi et al , 2010Shikama et al 2010).…”

“…For each BP, the ABRE is expressed relative to that of etidronate, which is shown as 1 (Geddes et al 1994). (Crépin et al 2010), and that clodronate does not induce acute inflammatory side effects in human patients (Adami et al 1987). Thus, it is questionable whether clodronate does indeed cause ONJ.…”