Case Report/Clinical Techniques
Bisphosphonate-associated Osteonecrosis of Jaw Reoccurrence after Methotrexate Therapy: A Case Report Fahd Alsalleeh, BDS, MS, PhD,*† Jeffery Keippel, DMD,* Lyde Adams, DMD,* and Bruce Bavitz, DMD* Abstract Introduction: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a well-known complication caused by amino-bisphosphonate therapy. We document one case of BRONJ associated with oral administration of methotrexate, a known immunosuppressive drug used to treat rheumatoid arthritis. Methods: A 66-year-old woman was referred for evaluation and endodontic surgery of recently re-treated tooth 13. Tooth 14 was extracted 3 months prior, and the extraction site had not completely healed. Her medical history revealed rheumatoid arthritis and osteoporosis. She had been taking Fosamax (alendronate) 70 mg daily. Because of adequate root canal therapy of tooth 13, endodontic surgery was performed. Five months after apicoectomy, her symptoms had not changed. Tooth 13 was extracted, and the socket healed without complications. The socket of extracted tooth 14 was also healing. At the 3-month recall visit, bone exposure and purulent discharge at the site of extracted tooth 14 were noted. The patient had recently received methotrexate. The methotrexate was discontinued, and she was given course of amoxicillin. Results: At the 18-month follow-up, the healing progressed, and the wound was closed. Conclusion: A medication that suppresses the immune system such as methotrexate may complicate the management of BRONJ. Once a diagnosis of BRONJ is made, a closely monitored conservative approach is recommended. (J Endod 2014;-:1–3)
Key Words Bone necrosis induced by bisphosphonate, methotrexate, rheumatoid arthritis
From the *Department of Surgical Specialties, College of Dentistry, University of Nebraska Medical Center, Lincoln, Nebraska; and †Department of Restorative Dental Sciences, College of Dentistry, King Saud University, Riyadh, Saudi Arabia. Address requests for reprints to Dr Fahd Alsalleeh, Department of Surgical Specialties, College of Dentistry, University of Nebraska Medical Center, 40th and Holdrege Streets, Lincoln, NE 68583. E-mail address: [email protected] 0099-2399/$ - see front matter Copyright ª 2014 American Association of Endodontists. http://dx.doi.org/10.1016/j.joen.2014.01.035
JOE — Volume -, Number -, - 2014
B
isphosphonates (BPs) are pyrophosphate analogs. When given at high doses, they inhibit ectopic calcification and bone resorption. Currently, BPs are mainly used as an inhibitor of bone resorption in patients diagnosed with diseases such as advanced breast cancer, multiple myeloma, Paget’s disease, hyperparathyroidism, and osteoporosis (1, 2). As a result of an increased number of patients taking the drug, numerous reports have been published in both medical and dental journals highlighting some adverse effects. These include outcomes not reported during clinical trials, oral mucosa ulceration and bisphosphonate-related osteonecrosis of the jaw (BRONJ) (3). The incidence of BRONJ varies and is based on limited retrospective uncontrolled studies. It is widely accepted that high-dose intravenous administration of BPs, coupled with traumatic dental surgery, puts the patient at high risk. Patients receiving oral BP therapy for osteoporosis are at a lower risk to develop BRONJ, but advanced age and immunosuppressive drugs such as steroids increase the risk (4). Reports of BRONJ with patients taking oral BPs are becoming more common. Many of these reports are in patients with rheumatoid arthritis (RA) (5, 6). There are 2 theories that could link RA and BRONJ, persistent inflammatory alterations from the disease itself and drugs used to treat RA (7). Methotrexate, an antimetabolite and antifolate drug, is considered a disease-modifying antirheumatic drug. It is widely used as soon as a patient is diagnosed with active RA. Despite its efficacy, its use is limited by associated serious adverse events that may lead to severe toxicity. It is still unknown whether methotrexate may be a risk factor to develop BRONJ. This report describes the course and therapeutic approach of one unpublished case of reoccurrence of BRONJ in a patient with RA after taking methotrexate.
Case Report In December 2010, a 66-year-old woman had the upper left first molar, tooth 14, extracted by a general dentist. The extraction site failed to heal, and the upper left second premolar, tooth 13, became symptomatic. Nonsurgical retreatment root canal therapy of tooth 13 was performed by an endodontist, who later referred the patient for evaluation of the upper left side because of persistent pain and purulent discharge. The patient was seen in February 2011 at the endodontic postgraduate clinic. A medical history revealed that the patient had RA and osteoporosis. Current medications at the time were Fosamax (alendronate) 70 mg (once weekly from March 2008–March 2011) for osteoporosis, Tylenol 650 mg every 6 hours, narcotic 5/325 mg every 6 hours for joint pain, promethazine with codeine syrup 6.25 mg/10 mg for cough, and folic acid 1 mg daily. The patient had no history of radiotherapy, tumors, or trauma. During the clinical examination, the socket of extracted tooth 14 was almost closed except for a small 2 2 mm area. A purulent discharge with no exposed bone was noted. Examination revealed a sinus tract that could be traced to a lesion related to tooth 13 (Fig. 1A). Tooth 13 was diagnosed as previously treated with a chronic apical abscess. Early stage of BRONJ was also considered. The patient was given the option of endodontic surgery or extraction of tooth 13. The patient elected to have the endodontic surgery and signed the consent form. Five months after the surgery, her symptoms had not changed. The patient was given repeated intermittent courses of amoxicillin 500 mg every 8 hours for 7 days. However, the operative site never closed. In November 2011, nine months after the endodontic surgery, tooth 13 was extracted because of the persistent related lesion
BRONJ Reoccurrence after Methotrexate Therapy
1
Case Report/Clinical Techniques
Figure 1. Preoperative radiographs of tooth 13 showing adequate nonsurgical root canal therapy with periapical radiolucency and sinus tract (A). Tooth 13 socket after extraction (B). The edentulous alveolar bone surrounded by inflamed soft tissue with evidence of purulent discharge at site of extracted tooth 14 (C).
(Fig. 1B). A 2-month regimen of amoxicillin was given as before, and her pain subsided, with wound healing almost complete. At the 3-month recall visit, the patient had bone exposure of the edentulous alveolar bone surrounded by inflamed soft tissue, with evidence of purulent discharge at the site of extracted tooth 14. The lesion progressed rapidly in 1 month (Fig. 1C). The patient indicated that because of her progressive RA, she had received methotrexate 12.5 mg once a week for the last 2 months. Two pieces of bone were taken from the site and submitted for scanning electron microscope (SEM) and histo-
pathologic analysis. Hematoxylin-eosin staining was used for histologic observation by light microscopy. Necrotic bone fragments with chronic inflammatory cells and abundant bacterial colonies were noted (Fig. 2A). Furthermore, SEM analyses showed evidence of sequestrate bone fragments filled with spherical red blood cells and biofilms (Fig. 2B). A letter was sent to her physician for a consultation, and the patient stopped taking methotrexate. Another 3-month course of amoxicillin was given. The patient was also given strict oral hygiene instructions and prescribed chlorhexidine 0.12% mouth rinse twice
Figure 2. Hematoxylin-eosin staining shows necrotic bone fragments with chronic and inflammatory cells, and abundant bacterial colonies were noted (A). SEM analyses showed evidence of sequestrate bone fragments filled with spherical red blood cells and biofilms; a higher magnification is indicated by the arrow (B). The edentulous alveolar bone was closed, and soft tissue healed with no signs of inflammatory or infectious process at 18 months (C and D). Periapical radiograph of healed extracted sites at 18 months (E).
2
Alsalleeh et al.
JOE — Volume -, Number -, - 2014
Case Report/Clinical Techniques daily. The healing progressed slowly, and the wound was closed with no signs of inflammatory or infectious process at 18 months (Fig. 2C, D). A periapical radiograph showed normal bone texture of the extraction sites and the edentulous alveolar bone (Fig. 2E).
Discussion Case reports of BRONJ associated with intravenous BP administration have been documented often. BRONJ frequency rates have been reported to be 1%–10% in different population groups (8). On the other hand, BRONJ reported with oral administration is less common. The majority of these cases have been reported in patients with osteoporosis or RA (6, 9, 10). Although there is no strong evidence that links RA and BRONJ, the case presented herein fits the profile of other cases reported in the literature. RA is a systemic immunologic disease characterized by persistent high level of proinflammatory cytokines and inflammatory cells. To prevent and treat osteoporosis, which is a common feature in RA, postmenopausal women are often given BPs (11). It is possible that the incidence of BRONJ will increase as a result of this practice. Drugs prescribed for patients with RA, including steroids and methotrexate, may play a major role in the development of BRONJ. Steroids can induce bone necrosis, predominantly in long bones, and does not produce bone exposure (12). Methotrexate inhibits the metabolism of folic acid. It is often used as a monotherapy or in combination with corticosteroids. Despite its dramatic improvement of clinical status and outcomes of many patients with RA, it may cause cytopenia, serious infections, liver damage, synovitis, systemic inflammation and disability, and mucocutaneous ulcers (11, 13). Certainly these adverse events may encourage the progress of BRONJ, and methotrexate seemed to change the course of healing in the current case. Recently a case of BRONJ that did not respond to teriparatide, a medication that exerts anabolic effect on bone that has been shown to be effective in the management of severe BRONJ resistant to conventional therapy (14), was recently reported. Interestingly enough, the patient had a depletion of B cell and impaired T-cell function as a result of methotrexate therapy, which may account for treatment failure (15). To the best of our knowledge, this is the first case with close observation to show that methotrexate may indeed be a risk factor for BRONJ. The patient had stopped taking BPs for almost 1 year, and healing was uneventful until she started taking methotrexate; bone exposure at the extraction site was then noted. In most cases reported so far, including the current case, BRONJ developed after invasive dental procedures such as tooth extraction. The present case highlights the challenges in diagnosis and treating these patients. Although BRONJ is considered uncommon, the dental profession also should identify risk factors and provide modified treatment to these patients. The unhealed socket in the present case was thought to be due to the persistent lesion on the tooth next to it, tooth 13. However, the lesion persisted and did not resolve after endodontic therapy and surgical intervention. The patient stopped taking BPs for 6 months, and tooth 13 was extracted,
JOE — Volume -, Number -, - 2014
which resulted in uneventful healing. It was interesting that the lesion reoccurred at the same site, tooth 14, and not tooth 13. This may imply that whether nonsurgical or surgical, endodontic treatment is considered to be safe. The histology and SEM analysis presented showed necrotic bone fragments with chronic and inflammatory cells and abundant bacterial colonies/biofilms. Management of the current case was mainly with the use of antiseptic mouthwashes (chlorhexidine) and a broad-spectrum antibiotic, amoxicillin. The key finding from this case was that methotrexate seemed to tip the scale from a slow healing surgical site to one of BRONJ. Nevertheless, prevention of BRONJ would be more important. All patients should have a thorough oral examination before starting them on BPs.
Acknowledgments The authors thank Dr Lane Stephenson for reviewing the manuscript. The authors deny any conflicts of interest related to this study.
References 1. Fleisch H. Bisphosphonates: mechanisms of action. Endocr Rev 1998;19:80–100. 2. Russell RG, Xia Z, Dunford JE, et al. Bisphosphonates: an update on mechanisms of action and how these relate to clinical efficacy. Ann N Y Acad Sci 2007;1117: 209–57. 3. Ruggiero SL. Bisphosphonate-related osteonecrosis of the jaw: an overview. Ann N Y Acad Sci 2011;1218:38–46. 4. Ruggiero SL, Dodson TB, Assael LA, et al. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws: 2009 update. J Oral Maxillofac Surg 2009;67:2–12. 5. Conti HR, Gaffen SL. Host responses to Candida albicans: Th17 cells and mucosal candidiasis. Microbes Infect 2010;12:518–27. 6. Park W, Kim NK, Kim MY, et al. Osteonecrosis of the jaw induced by oral administration of bisphosphonates in Asian population: five cases. Osteoporos Int 2010;21: 527–33. 7. Conte Neto N, Bastos AS, Chierici-Marcantonio RA, Marcantonio E Jr. Is rheumatoid arthritis a risk factor for oral bisphosphonate-induced osteonecrosis of the jaws? Med Hypotheses 2011;77:905–11. 8. McLeod NM, Brennan PA, Ruggiero SL. Bisphosphonate osteonecrosis of the jaw: a historical and contemporary review. Surgeon 2012;10:36–42. 9. Malden NJ, Pai AY. Oral bisphosphonate associated osteonecrosis of the jaws: three case reports. Br Dent J 2007;203:93–7. 10. Conte-Neto N, Bastos AS, Spolidorio LC, et al. Oral bisphosphonate-related osteonecrosis of the jaws in rheumatoid arthritis patients: a critical discussion and two case reports. Head Face Med 2011;7:7. 11. Scott DL. Biologics-based therapy for the treatment of rheumatoid arthritis. Clin Pharmacol Ther 2012;91:30–43. 12. Powell C, Chang C, Naguwa SM, et al. Steroid induced osteonecrosis: an analysis of steroid dosing risk. Autoimmun Rev 2010;9:721–43. 13. Salliot C, van der Heijde D. Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: a systematic literature research. Ann Rheum Dis 2009;68:1100–4. 14. Cheung A, Seeman E. Teriparatide therapy for alendronate-associated osteonecrosis of the jaw. N Engl J Med 2010;363:2473–4. 15. Narvaez J, Narvaez JA, Gomez-Vaquero C, Nolla JM. Lack of response to teriparatide therapy for bisphosphonate-associated osteonecrosis of the jaw. Osteoporos Int 2013;24:731–3.
BRONJ Reoccurrence after Methotrexate Therapy
3
Bisphosphonate-associated Osteonecrosis of Jaw Reoccurrence after Methotrexate Therapy: A Case Report Fahd Alsalleeh, BDS, MS, PhD,*† Jeffery Keippel, DMD,* Lyde Adams, DMD,* and Bruce Bavitz, DMD* Abstract Introduction: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a well-known complication caused by amino-bisphosphonate therapy. We document one case of BRONJ associated with oral administration of methotrexate, a known immunosuppressive drug used to treat rheumatoid arthritis. Methods: A 66-year-old woman was referred for evaluation and endodontic surgery of recently re-treated tooth 13. Tooth 14 was extracted 3 months prior, and the extraction site had not completely healed. Her medical history revealed rheumatoid arthritis and osteoporosis. She had been taking Fosamax (alendronate) 70 mg daily. Because of adequate root canal therapy of tooth 13, endodontic surgery was performed. Five months after apicoectomy, her symptoms had not changed. Tooth 13 was extracted, and the socket healed without complications. The socket of extracted tooth 14 was also healing. At the 3-month recall visit, bone exposure and purulent discharge at the site of extracted tooth 14 were noted. The patient had recently received methotrexate. The methotrexate was discontinued, and she was given course of amoxicillin. Results: At the 18-month follow-up, the healing progressed, and the wound was closed. Conclusion: A medication that suppresses the immune system such as methotrexate may complicate the management of BRONJ. Once a diagnosis of BRONJ is made, a closely monitored conservative approach is recommended. (J Endod 2014;-:1–3)
Key Words Bone necrosis induced by bisphosphonate, methotrexate, rheumatoid arthritis
From the *Department of Surgical Specialties, College of Dentistry, University of Nebraska Medical Center, Lincoln, Nebraska; and †Department of Restorative Dental Sciences, College of Dentistry, King Saud University, Riyadh, Saudi Arabia. Address requests for reprints to Dr Fahd Alsalleeh, Department of Surgical Specialties, College of Dentistry, University of Nebraska Medical Center, 40th and Holdrege Streets, Lincoln, NE 68583. E-mail address: [email protected] 0099-2399/$ - see front matter Copyright ª 2014 American Association of Endodontists. http://dx.doi.org/10.1016/j.joen.2014.01.035
JOE — Volume -, Number -, - 2014
B
isphosphonates (BPs) are pyrophosphate analogs. When given at high doses, they inhibit ectopic calcification and bone resorption. Currently, BPs are mainly used as an inhibitor of bone resorption in patients diagnosed with diseases such as advanced breast cancer, multiple myeloma, Paget’s disease, hyperparathyroidism, and osteoporosis (1, 2). As a result of an increased number of patients taking the drug, numerous reports have been published in both medical and dental journals highlighting some adverse effects. These include outcomes not reported during clinical trials, oral mucosa ulceration and bisphosphonate-related osteonecrosis of the jaw (BRONJ) (3). The incidence of BRONJ varies and is based on limited retrospective uncontrolled studies. It is widely accepted that high-dose intravenous administration of BPs, coupled with traumatic dental surgery, puts the patient at high risk. Patients receiving oral BP therapy for osteoporosis are at a lower risk to develop BRONJ, but advanced age and immunosuppressive drugs such as steroids increase the risk (4). Reports of BRONJ with patients taking oral BPs are becoming more common. Many of these reports are in patients with rheumatoid arthritis (RA) (5, 6). There are 2 theories that could link RA and BRONJ, persistent inflammatory alterations from the disease itself and drugs used to treat RA (7). Methotrexate, an antimetabolite and antifolate drug, is considered a disease-modifying antirheumatic drug. It is widely used as soon as a patient is diagnosed with active RA. Despite its efficacy, its use is limited by associated serious adverse events that may lead to severe toxicity. It is still unknown whether methotrexate may be a risk factor to develop BRONJ. This report describes the course and therapeutic approach of one unpublished case of reoccurrence of BRONJ in a patient with RA after taking methotrexate.
Case Report In December 2010, a 66-year-old woman had the upper left first molar, tooth 14, extracted by a general dentist. The extraction site failed to heal, and the upper left second premolar, tooth 13, became symptomatic. Nonsurgical retreatment root canal therapy of tooth 13 was performed by an endodontist, who later referred the patient for evaluation of the upper left side because of persistent pain and purulent discharge. The patient was seen in February 2011 at the endodontic postgraduate clinic. A medical history revealed that the patient had RA and osteoporosis. Current medications at the time were Fosamax (alendronate) 70 mg (once weekly from March 2008–March 2011) for osteoporosis, Tylenol 650 mg every 6 hours, narcotic 5/325 mg every 6 hours for joint pain, promethazine with codeine syrup 6.25 mg/10 mg for cough, and folic acid 1 mg daily. The patient had no history of radiotherapy, tumors, or trauma. During the clinical examination, the socket of extracted tooth 14 was almost closed except for a small 2 2 mm area. A purulent discharge with no exposed bone was noted. Examination revealed a sinus tract that could be traced to a lesion related to tooth 13 (Fig. 1A). Tooth 13 was diagnosed as previously treated with a chronic apical abscess. Early stage of BRONJ was also considered. The patient was given the option of endodontic surgery or extraction of tooth 13. The patient elected to have the endodontic surgery and signed the consent form. Five months after the surgery, her symptoms had not changed. The patient was given repeated intermittent courses of amoxicillin 500 mg every 8 hours for 7 days. However, the operative site never closed. In November 2011, nine months after the endodontic surgery, tooth 13 was extracted because of the persistent related lesion
BRONJ Reoccurrence after Methotrexate Therapy
1
Case Report/Clinical Techniques
Figure 1. Preoperative radiographs of tooth 13 showing adequate nonsurgical root canal therapy with periapical radiolucency and sinus tract (A). Tooth 13 socket after extraction (B). The edentulous alveolar bone surrounded by inflamed soft tissue with evidence of purulent discharge at site of extracted tooth 14 (C).
(Fig. 1B). A 2-month regimen of amoxicillin was given as before, and her pain subsided, with wound healing almost complete. At the 3-month recall visit, the patient had bone exposure of the edentulous alveolar bone surrounded by inflamed soft tissue, with evidence of purulent discharge at the site of extracted tooth 14. The lesion progressed rapidly in 1 month (Fig. 1C). The patient indicated that because of her progressive RA, she had received methotrexate 12.5 mg once a week for the last 2 months. Two pieces of bone were taken from the site and submitted for scanning electron microscope (SEM) and histo-
pathologic analysis. Hematoxylin-eosin staining was used for histologic observation by light microscopy. Necrotic bone fragments with chronic inflammatory cells and abundant bacterial colonies were noted (Fig. 2A). Furthermore, SEM analyses showed evidence of sequestrate bone fragments filled with spherical red blood cells and biofilms (Fig. 2B). A letter was sent to her physician for a consultation, and the patient stopped taking methotrexate. Another 3-month course of amoxicillin was given. The patient was also given strict oral hygiene instructions and prescribed chlorhexidine 0.12% mouth rinse twice
Figure 2. Hematoxylin-eosin staining shows necrotic bone fragments with chronic and inflammatory cells, and abundant bacterial colonies were noted (A). SEM analyses showed evidence of sequestrate bone fragments filled with spherical red blood cells and biofilms; a higher magnification is indicated by the arrow (B). The edentulous alveolar bone was closed, and soft tissue healed with no signs of inflammatory or infectious process at 18 months (C and D). Periapical radiograph of healed extracted sites at 18 months (E).
2
Alsalleeh et al.
JOE — Volume -, Number -, - 2014
Case Report/Clinical Techniques daily. The healing progressed slowly, and the wound was closed with no signs of inflammatory or infectious process at 18 months (Fig. 2C, D). A periapical radiograph showed normal bone texture of the extraction sites and the edentulous alveolar bone (Fig. 2E).
Discussion Case reports of BRONJ associated with intravenous BP administration have been documented often. BRONJ frequency rates have been reported to be 1%–10% in different population groups (8). On the other hand, BRONJ reported with oral administration is less common. The majority of these cases have been reported in patients with osteoporosis or RA (6, 9, 10). Although there is no strong evidence that links RA and BRONJ, the case presented herein fits the profile of other cases reported in the literature. RA is a systemic immunologic disease characterized by persistent high level of proinflammatory cytokines and inflammatory cells. To prevent and treat osteoporosis, which is a common feature in RA, postmenopausal women are often given BPs (11). It is possible that the incidence of BRONJ will increase as a result of this practice. Drugs prescribed for patients with RA, including steroids and methotrexate, may play a major role in the development of BRONJ. Steroids can induce bone necrosis, predominantly in long bones, and does not produce bone exposure (12). Methotrexate inhibits the metabolism of folic acid. It is often used as a monotherapy or in combination with corticosteroids. Despite its dramatic improvement of clinical status and outcomes of many patients with RA, it may cause cytopenia, serious infections, liver damage, synovitis, systemic inflammation and disability, and mucocutaneous ulcers (11, 13). Certainly these adverse events may encourage the progress of BRONJ, and methotrexate seemed to change the course of healing in the current case. Recently a case of BRONJ that did not respond to teriparatide, a medication that exerts anabolic effect on bone that has been shown to be effective in the management of severe BRONJ resistant to conventional therapy (14), was recently reported. Interestingly enough, the patient had a depletion of B cell and impaired T-cell function as a result of methotrexate therapy, which may account for treatment failure (15). To the best of our knowledge, this is the first case with close observation to show that methotrexate may indeed be a risk factor for BRONJ. The patient had stopped taking BPs for almost 1 year, and healing was uneventful until she started taking methotrexate; bone exposure at the extraction site was then noted. In most cases reported so far, including the current case, BRONJ developed after invasive dental procedures such as tooth extraction. The present case highlights the challenges in diagnosis and treating these patients. Although BRONJ is considered uncommon, the dental profession also should identify risk factors and provide modified treatment to these patients. The unhealed socket in the present case was thought to be due to the persistent lesion on the tooth next to it, tooth 13. However, the lesion persisted and did not resolve after endodontic therapy and surgical intervention. The patient stopped taking BPs for 6 months, and tooth 13 was extracted,
JOE — Volume -, Number -, - 2014
which resulted in uneventful healing. It was interesting that the lesion reoccurred at the same site, tooth 14, and not tooth 13. This may imply that whether nonsurgical or surgical, endodontic treatment is considered to be safe. The histology and SEM analysis presented showed necrotic bone fragments with chronic and inflammatory cells and abundant bacterial colonies/biofilms. Management of the current case was mainly with the use of antiseptic mouthwashes (chlorhexidine) and a broad-spectrum antibiotic, amoxicillin. The key finding from this case was that methotrexate seemed to tip the scale from a slow healing surgical site to one of BRONJ. Nevertheless, prevention of BRONJ would be more important. All patients should have a thorough oral examination before starting them on BPs.
Acknowledgments The authors thank Dr Lane Stephenson for reviewing the manuscript. The authors deny any conflicts of interest related to this study.
References 1. Fleisch H. Bisphosphonates: mechanisms of action. Endocr Rev 1998;19:80–100. 2. Russell RG, Xia Z, Dunford JE, et al. Bisphosphonates: an update on mechanisms of action and how these relate to clinical efficacy. Ann N Y Acad Sci 2007;1117: 209–57. 3. Ruggiero SL. Bisphosphonate-related osteonecrosis of the jaw: an overview. Ann N Y Acad Sci 2011;1218:38–46. 4. Ruggiero SL, Dodson TB, Assael LA, et al. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws: 2009 update. J Oral Maxillofac Surg 2009;67:2–12. 5. Conti HR, Gaffen SL. Host responses to Candida albicans: Th17 cells and mucosal candidiasis. Microbes Infect 2010;12:518–27. 6. Park W, Kim NK, Kim MY, et al. Osteonecrosis of the jaw induced by oral administration of bisphosphonates in Asian population: five cases. Osteoporos Int 2010;21: 527–33. 7. Conte Neto N, Bastos AS, Chierici-Marcantonio RA, Marcantonio E Jr. Is rheumatoid arthritis a risk factor for oral bisphosphonate-induced osteonecrosis of the jaws? Med Hypotheses 2011;77:905–11. 8. McLeod NM, Brennan PA, Ruggiero SL. Bisphosphonate osteonecrosis of the jaw: a historical and contemporary review. Surgeon 2012;10:36–42. 9. Malden NJ, Pai AY. Oral bisphosphonate associated osteonecrosis of the jaws: three case reports. Br Dent J 2007;203:93–7. 10. Conte-Neto N, Bastos AS, Spolidorio LC, et al. Oral bisphosphonate-related osteonecrosis of the jaws in rheumatoid arthritis patients: a critical discussion and two case reports. Head Face Med 2011;7:7. 11. Scott DL. Biologics-based therapy for the treatment of rheumatoid arthritis. Clin Pharmacol Ther 2012;91:30–43. 12. Powell C, Chang C, Naguwa SM, et al. Steroid induced osteonecrosis: an analysis of steroid dosing risk. Autoimmun Rev 2010;9:721–43. 13. Salliot C, van der Heijde D. Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: a systematic literature research. Ann Rheum Dis 2009;68:1100–4. 14. Cheung A, Seeman E. Teriparatide therapy for alendronate-associated osteonecrosis of the jaw. N Engl J Med 2010;363:2473–4. 15. Narvaez J, Narvaez JA, Gomez-Vaquero C, Nolla JM. Lack of response to teriparatide therapy for bisphosphonate-associated osteonecrosis of the jaw. Osteoporos Int 2013;24:731–3.
BRONJ Reoccurrence after Methotrexate Therapy
3
