Methotrexate-related osteonecrosis of the jaw: Report of two cases

Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology 29 (2017) 546–549

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Case report

Methotrexate-related osteonecrosis of the jaw: Report of two cases夽 Toru Komatani ∗ , Junya Sonobe, Katsu Takahashi, Kazuhisa Bessho Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan

a r t i c l e

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Article history: Received 24 January 2017 Received in revised form 18 March 2017 Accepted 17 June 2017 Available online 24 June 2017 Keywords: Methotrexate/AE Osteonecrosis Hyperbaric oxygen therapy

a b s t r a c t Although methotrexate (MTX) is widely used to treat malignancies and autoimmune diseases, it is associated with a range of adverse effects. We report the cases of two men aged 88 and 73 years who were treated with MTX for rheumatoid arthritis and who both presented with exposed bone in the jaw, characteristic of osteonecrosis. We saw no change in symptoms in the first patient while MTX was being administered, while expansion of the jaw and bone exposure stopped immediately after cessation of MTX in the second case. We therefore suspected that both cases were MTX-related osteonecrosis of the jaw. Osteonecrosis has been reported with drugs that are not among those recognized as causing medication-related osteonecrosis of the jaw. Dentists and oral surgeons must carefully examine the oral cavity of patients on MTX therapy as part of regular practice. © 2017 Asian AOMS, ASOMP, JSOP, JSOMS, JSOM, and JAMI. Published by Elsevier Ltd. All rights reserved.夽

1. Introduction Methotrexate (MTX) is used to treat malignancies, including leukemia, and autoimmune diseases such as rheumatoid arthritis (RA), and is frequently used as first-line therapy for RA worldwide [1]. MTX has been associated with a range of adverse effects, including myelopathy, interstitial pneumonia (MTX pneumonia), and MTX-associated lymphoproliferative disorder (MTX-LPD). However, we are unaware of any report of MTX-related osteonecrosis of the jaw with bone exposure. Here, we report two cases of MTXrelated osteonecrosis of the jaw. 2. Case report 2.1. Case 1 An 88-year-old man underwent extraction of the upper right second premolar at a dental clinic in January 2013. In July 2013 he visited our department due to ongoing drainage from the extraction site. His medical history included RA, bladder cancer, and prostate cancer. He had no evidence of bone metastases from either malig-

夽 AsianAOMS: Asian Association of Oral and Maxillofacial Surgeons; ASOMP: Asian Society of Oral and Maxillofacial Pathology; JSOP: Japanese Society of Oral Pathology; JSOMS: Japanese Society of Oral and Maxillofacial Surgeons; JSOM: Japanese Society of Oral Medicine; JAMI: Japanese Academy of Maxillofacial Implants. ∗ Corresponding author. E-mail address: [email protected] (T. Komatani).

nancy. His RA had been treated with MTX 4 mg once weekly since 2013. Physical examination revealed exposed bone at the extraction site (Fig. 1A). CT revealed a sequestrum in the right maxillary sinus floor surrounded by soft tissue (Fig. 1B and C), while bone scintigraphy showed the accumulation of radiotracer in the right upper molar region and right maxilla (Fig. 1D–F). Blood tests revealed a mild increase in inflammatory markers. Based on these clinical findings, the lesion was diagnosed as osteonecrosis of the maxilla with a sequestrum and maxillary sinusitis. Administration of antibiotics and regular irrigation with saline via a syringe commenced in July 2013 on an outpatient basis. Although the drainage stopped, the exposed bone at the extraction site remained. The patient developed primary rectal cancer and underwent surgery. He died in October 2014. 2.2. Case 2 A 73-year-old man became aware of left lower occlusal pain in July 2013 and developed paresthesias in the left mental region in December. His past medical history included RA, abdominal aortic aneurysm, and angina pectoris. The RA has been treated with MTX 6 mg once weekly and prednisolone 7.5 mg once daily since 2011. Physical examination revealed bone exposure in the left upper first molar and left lower second molar gingiva (Fig. 2A and B). CT showed bone resorption around the left lower second molar apex without associated osteosclerosis (Fig. 2C and D) and bone scintigraphy revealed increased uptake in the involved regions (Fig. 2E–G). Blood test values revealed reference values. Based on these clinical findings, the lesion was diagnosed as osteonecrosis of the left maxilla and mandible.

http://dx.doi.org/10.1016/j.ajoms.2017.06.009 2212-5558/© 2017 Asian AOMS, ASOMP, JSOP, JSOMS, JSOM, and JAMI. Published by Elsevier Ltd. All rights reserved.夽

T. Komatani et al. / Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology 29 (2017) 546–549

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Fig. 1. Case 1. Bone exposure was probed in the upper right extraction site (yellow arrow indicates bone exposure) (A). Separation of a sequestrum was noted in the right maxillary sinus floor on computed tomography images (yellow arrows indicate separation of a sequestrum) (B) and (C). Radiotracer accumulation was detected in the right upper molar region on bone scintigraphy (D: anterior), (E: coronal), (F: axial). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Outpatient hyperbaric oxygen therapy (HBO) and administration of antibiotics were initiated, but the lesions enlarged (Fig. 2H and I). A sequestration developed, small sections of which were removed at several sessions of debridement. On biopsy of the exposed bone (left upper second premolar and left upper second molar lingual alveolar bone) and surrounding gingiva (left upper second molar and left lower second premolar lingual gingiva), histopathology showed gingival inflammation and necrotic bone, with a sequestrum in the exposed bone (left upper second premolar and left upper second molar lingual alveolar bone). No tumor cells, atypical cells, or atypical lymphocytes found in MTX-LPD were identified (Fig. 2J and K). Despite ongoing inpatient treatment with HBO and antibiotics, expansion of the areas of bone exposure occurred, with no epithelialization or separation of the sequestration. After consultation with our rheumatologist, therapy was changed to tacrolimus 14 mg once weekly, which resulted in improvement, with shrinkage of the exposed areas and partial epithelialization. Additional debridement and extraction of the left lower first molar and second premolar pontic was performed, with further improvement (Fig. 2L and M). 3. Discussion MTX is an antifolate which exhibits various cell growthinhibitory effects by suppressing DNA synthesis through the inhibition of dihydrofolate reductase. It mainly inhibits the growth of lymphocyte system cells, exhibiting strong immunosuppressive and anti-inflammatory actions. However, MTX induces a range of adverse reactions, including myelopathy, interstitial pneumonia (MTX pneumonia), infection, liver disorders, and MTX-LPD. Ellman et al. first reported LPD in MTX-treated RA patients in 1991 [2], and since that time the number of cases has continued

to increase. However, the mechanism of MTX-LPD remains to be determined. Suggested hypotheses include infection with EBV in an MTX-induced immunosuppressed state, reactivation-induced growth of immortalized B cells, and the involvement of RA in the immunopathogenesis [3]. Our patients were both diagnosed with osteonecrosis of the jaw. Histopathologically, we did not recognize the variety of atypical lymphocytes typically present in MTX-LPD or abnormal lymphocytes present in hematopoietic tumor in the specimen from Case 2. Several cases of MTX-LPD accompanied by osteonecrosis of the jaw have been reported [4]. Bone necrosis in MTX-LPD may occur as a result of an opportunistic infection and malignant invasion of bone. In our cases, bone exposure was considered not due to MTXLPD and malignant cells were not detected on histopathological examination. For case 2, prednisolone had been administered at 7.5 mg once daily since 2011, and osteonecrosis due to glucocorticoid side effects was considered. Zizic et al. reported that the mean daily dose of prednisone exceeded 40 mg/day for ≥1 month in 93% of patients and 20 mg/day in 100% of patients who developed osteonecrosis. For this case, we considered that the relationship of osteonecrosis of the jaw with prednisolone was negative because the dose was low [5]. The American Association of Oral and Maxillofacial Surgeons (AAOMS) position paper on Medication-related Osteonecrosis of the Jaw (MRONJ) has reported a growing incidence of osteonecrosis cases involving the maxilla and mandible associated with bisphosphonates, anti-receptor activator nuclear factor kappa ␤ ligand (anti-RANKL) (denosumab) and antiangiogenic therapies [6]. The MRONJ case definition is current or previous treatment with antiresorptive or antiangiogenic agents, exposed bone or bone that can be probed through an intraoral or extraoral fistula in the maxillofacial region that has persisted for longer than 8 weeks, and

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T. Komatani et al. / Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology 29 (2017) 546–549

no history of radiation therapy to the jaws or obvious metastatic disease to the jaws [6]. Proposed hypotheses that attempt to explain the pathophysiology include inhibition of osteoclastic bone resorption and remodeling, inflammation or infection, inhibition of angiogenesis, microdamage, vitamin D deficiency, mechanical injury, bisphosphonate toxicity to soft tissues, and suppression of innate or acquired immunity [6]. Regarding management, the position paper provided treatment strategies for each stage. Stage 2 is defined as exposed and necrotic bone or a fistula that probes to bone with evidence of infection. These patients benefit from the use of an oral antimicrobial rinse in combination with antibiotic therapy. Operative therapy directed at reducing the volume of colonized necrotic bone may serve as a beneficial adjunct to antibiotic therapy [6]. The Journal of Bone and Mineral Research (JBMR) International Consensus for Osteonecrosis of the Jaw (ONJ) reported that ONJ has been described in several patients treated for cancer with antiangiogenic agents, such as sunitinib and bevacizumab [7]. Regarding management, an international consensus panel determined that treatment strategies depend on disease stage, and range from conservative nonsurgical therapy to early surgical intervention. They recommend adjunctive therapy with HBO in combination with surgery in Stage 2 [7]. MTX has been reported to exert a direct effect on osteoclast differentiation. MTX inhibits osteon-osteoclast differentiation and inhibits osteoclastogenesis by decreasing RANKL-induced calcium influx into osteoclast progenitors, and subsequent NFATc1 activation and osteoclast differentiation [8]. In addition, MTX reportedly inhibits both fibroblast growth factor (FGF)- and vascular endothelial growth factor (VEGF)-stimulated DNA synthesis by human endothelial cells in vitro and suppresses VEGF-induced neovascularization in vivo [9]. Yang et al. reported that VEGF is an essential mediator during angiogenesis, and is active in both endochondral ossification and intramembranous ossification [10,11]. We therefore consider that MTX influenced not only bone angiogenesis in our cases, but also various aspects of bone development, including chondrocyte differentiation, osteoblast differentiation and osteoclast recruitment. We saw no change in symptoms in Case 1 while MTX was being used, while expansion of the jaw bone exposure stopped immediately after the cessation of MTX in Case 2. In both cases, no bisphosphonate, anti-RANKL, or antiangiogenic drugs were administered, and we suspect that both cases were MTX-related osteonecrosis of the jaw. Osteonecrosis in other parts of the skeleton has been linked to drugs not associated with osteonecrosis of the jaw. The role of steroids is still controversial [12,13]. Dentists and oral surgeons need to be alert to this potential complication in patients on MTX therapy. Conflicts of interest Fig. 2. Case 2. Bone exposure in the left upper and lower molar gingiva accompanied by redness (yellow arrows indicate bone exposure) (A) and (B). Bone resorption was noted around the left lower second molar apical part, but increased hardening was not noted (yellow arrows indicate bone resorption around the root) (C) and (D). Radiotracer accumulation was detected in the left upper and lower molar region (E)–(G). The start of outpatient hyperbaric oxygen therapy (HBO) and administration of antibiotics for bone exposure were accompanied by a rapid expansion in bone exposure (yellow arrows indicate bone exposure) (H) and (I). On histopathology the bone was necrotic with no osteocytes in the empty lacunae (yellow arrow indicates empty lacunae) (J). The gingiva was infiltrated by inflammatory cells in the submucosal layer (yellow arrow indicates inflammatory cells) (K). No tumor cells, atypical cells, or variety of atypical lymphocytes were present around the exposed bone region on biopsy. Bar = 100 ␮m (J) and (K). Expansion of bone exposure slowed after the change in treatment, and the bone exposure showed epithelialization, with repeated surgical removal of small amounts of sequestration at surgery (yellow arrow indicates epithelialization of exposed bone) (L). The left lower first molar and second premolar pontic were extracted because they were difficult to save (yellow arrow indicates epithelialization of exposed bone) (M). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

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