A case of early detection of bisphosphonate-related osteonecrosis of the jaw.

Osteonecrosis of the jaws is an adverse reaction associated with the use of bisphosphonates. Although the diagnosis of bisphosphonate-related osteonecrosis of the jaw (BRONJ) is based on symptomatology, it is often detected late because the patients become symptomatic only after osteonecrosis is well established. We describe a case of early oral BRONJ detected by magnetic resonance imaging (MRI) accidentally. Head MRI revealed low signal of T1-weight images in left mandibula. Patient had been treated with minodronate for osteoporosis during 18 months. Based on the MRI findings and medication history, early stage BRONJ could be considered. Therefore minodronate was switched to teriparatide. Thereafter mandible pares-thesias, odontalgia and exposed bone were not observed. This case suggests that MRI is useful for the early detection of BRONJ.

Introduction

Since 2003, osteonecrosis of the jaw has been associated with the use of bisphosphonates.[1] We describe a case of early oral bisphosphonate-related osteonecrosis of the jaw (BRONJ) detected by magnetic resonance imaging (MRI) that was performed accidentally, which could avoid the deterioration of this adverse reaction. To the best of our knowledge, this is the first report of BRONJ associated with minodronate, which caused BRONJ in a shorter duration compared with other bisphosphonates. Furthermore, like our case, there has been rarely the case of early stage of BRONJ, which revealed about image findings.

Case Report

A 69-year-old woman with a history of rheumatoid arthritis, hypertension and osteoporosis was admitted to our hospital complaining of vertigo. Her height was 152 cm, and she weighed 55 kg. Because of the suspicion of cerebral infarction, head MRI was performed and it revealed no fresh infarction. However, head MRI showed low signal of T1-weight and fluid-attenuated-inversion-recovery (FLAIR) images in left mandibular [Figure 1]. She had no history of exodontia and dental surgery while oral symptoms of mandible paresthesias, odontalgia and exposed bone were not observed on admission. She was prescribed methotrexate 6 mg/week, folic acid 5 mg/week, brotizolam 0.25 mg/day, prednisolone 3 mg/day, meloxicam 10 mg/day, amlodipine 5 mg/day, doxazosin 1 mg/day, alfacalcidol 0.5 μg/day and minodronate 50 mg/month before admission. According to her medication history, minodronate was started for osteoporosis 18 months before admission. At the time of admission, blood investigation were within normal range. Based on the MRI findings and medication history, early stage BRONJ could be considered, therefore minodronate was switched to recombinant human parathyroid hormone, teriparatide subcutaneous injection 20 μg/day. On the next day, vertigo was disappeared and she was discharged from our hospital because she had no evidence of fresh cerebral infarction. Until date, medical examination in her family clinic has been showed no evidence of mandible paresthesias, odontalgia and exposed bone.

Figure 1

Magnetic resonance imaging of this patient. (a) Fluid-attenuated-inversion-recovery coronal image shows low signal change in left mandible (thin arrow). (b) T1-weight sagittal image shows low signal change in left mandible (thick arrow)

Discussion

The exact underlying mechanism of BRONJ still remains not fully understood. Bisphosphonates inhibit endothelial proliferation and angiogenic effects, interrupting intraosseous circulation and bone blood flow, contributing to the development of BRONJ.[2] Mandibles affected by bisphosphonates appear to have less capability of repair by physiological mastication, suggested that the resulting unrepaired micro damage forms the stage for osteonecrosis.[2]

Minodronate is the first nitrogen-containing bisphosphonate developed and approved for osteoporosis in Japan.[3] With regard to inhibition of bone turnover, minodronate is 10-100 times more effective than alendronate because nitrogen-containing bisphosphonates have much stronger anti-bone turnover effects than nonnitrogen-containing bisphosphonates such as alendronate.[3] In other nitrogen-containing bisphosphonates such as zoledronate, the highest risk of BRONJ has been reported because of their strong anti-bone turnover effects. Unlike other nitrogen-containing bisphosphonates, BRONJ associated with minodronate has not been ever reported. However, it has been reported that minodronate's anti-boneresorptive effect and its necrotic effect were as great as, or greater than those of zoledronate in mice.[3] These results suggest that careful attention should be paid to the development of BRONJ in patients with minodronate as with other nitrogen-containing bisphosphonates. In the clinical study of patients with BRONJ, the mean duration of the zoledronate and alendronate treatments was 25 months and 88 months respectively.[2] On the other hand, duration of minodronate therapy in our case was 18 months. To our knowledge, our case is the first report of osteonecrosis of the jaw associated with minodronate, which caused BRONJ in a shorter duration compared with other bisphosphonates. These findings seem to be according with the degree of anti-boneresorptive effect of each bisphosphonates.

The most important risk factors are invasive oral treatments such as exodontia.[2] However, spontaneous cases have also been reported as seen in our case. Other risk factors of BRONJ include poorly controlled diabetes and other immunocompromised states, steroid treatment, chemotherapy, immunosuppressive therapy, advanced age, alcohol abuse and smoking.[2] Our patient also had multiple risk factors for BRONJ (steroid treatment, immunosuppressive therapy such as methotrexate, advanced age). Considering that bisphosphonates, steroid and methotrexate are among the most frequently prescribed drugs in rheumatologic practice, we should aware of the potential risk for BRONJ in patients with rheumatoid arthritis. Because osteonecrosis of the jaw has been recently described in patients treated with other medications, a more general term of this complication, medication-related osteonecrosis of the jaw, is proposed.[4]

According to the Naranjo adverse drug reaction probability scale,[5] BRONJ was probably related to minodronate administration in this case (score 5). Oral symptoms such as mandible paresthesias, odontalgia and exposed bone were not observed in our case when BRONJ was considered based on the MRI findings and medication history. From these findings, our case could be considered to be the early stage of BRONJ. To date, there have been few cases of the early stage of BRONJ because the patients become symptomatic only after osteonecrosis is well established. Furthermore, there have been few cases of BRONJ which revealed about image findings in an early stage. In our case, head MRI showed a low signal of T1-weight and FLAIR images in left mandibular [Figure 1]. In general, BRONJ displays low signal intensity on T1-weight sequences as with our case.[6] T1-weight and FLAIR images may show focal low signal because early stage of BRONJ is often accompanied with edema.[6]

Our report has three limitations. First, the image findings of BRONJ are not specific and are also found in other conditions such as osteomyelitis and cancer metastasis.[6] However, there was no evidence to suspect osteomyelitis or cancer metastasis in our case. In addition to the MRI findings, based on the medication history, minodronate's bone necrotic effect,[3] and Naranjo adverse drug reaction probability scale,[5] BRONJ could be considered in our case. Second, this case was not in agreement with diagnosis criteria of BRONJ because there was not exposed bone in the maxillofacial region. However, it is difficult to detect early stage of BRONJ by using current diagnosis criteria because exposed bone in the maxillofacial region is observed only after osteonecrosis is well established. Furthermore, even advanced cases can also occur without bone exposure in the maxillofacial region.[7] Appropriate diagnosis criteria of early stage BRONJ is required for early detection of BRONJ. Third, MRI image after switching from minodronate to teriparatide has been unclear because our patient returned from our hospital to her family clinic.

Conclusion

Our patient could avoid surgical treatment and deterioration of BRONJ by early detection using MRI. Furthermore, this case revealed the image findings in the early stage of BRONJ, which suggests that MRI is useful for the early detection of BRONJ.