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 Table of Contents  
CASE REPORT
Year : 2015  |  Volume : 27  |  Issue : 4  |  Page : 576-579

Medication-related osteonecrosis of the jaw in a patient with multiple myeloma


Department of Oral Medicine and Radiology, Mahatma Gandhi Postgraduate Institute of Dental Sciences, Puducherry, India

Date of Submission20-Oct-2015
Date of Acceptance24-May-2016
Date of Web Publication19-Aug-2016

Correspondence Address:
Dr. Nupur Bhardwaj
Department of Oral Medicine and Radiology, Mahatma Gandhi Postgraduate Institute of Dental Sciences, Puducherry - 605 006
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0972-1363.188766

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   Abstract 

Osteonecrosis of jaws is a common complication of parenteral nitrogen-containing bisphosphonates and recently medication-related osteonecrosis of the jaw (MRONJ) is contributing to the growing number of similar osteonecrosis cases which involve maxilla and mandible associated with other anti-resorptive and anti-angiogenic therapies. A 70-year-old male patient with multiple myeloma and discontinued chemotherapy reported with non-healing extraction site for past 1 year. He also complained of pus discharge extraorally for past 3 months. This case report describes the imaging findings of multiple myeloma in mandible and MRONJ.

Keywords: Medication-related osteonecrosis of the jaw, multiple myeloma, zoledronate


How to cite this article:
Bhardwaj N, Daniel MJ, Srinivasan SV, Jimsha VK. Medication-related osteonecrosis of the jaw in a patient with multiple myeloma. J Indian Acad Oral Med Radiol 2015;27:576-9

How to cite this URL:
Bhardwaj N, Daniel MJ, Srinivasan SV, Jimsha VK. Medication-related osteonecrosis of the jaw in a patient with multiple myeloma. J Indian Acad Oral Med Radiol [serial online] 2015 [cited 2022 Oct 3];27:576-9. Available from: https://www.jiaomr.in/text.asp?2015/27/4/576/188766


   Introduction Top


Multiple myeloma (MM) accounts for 10% of hematologic malignancies and it is characterized by neoplastic proliferation of plasma cell clones. [1] The most frequent complications are anemia, renal failure, recurrent bacterial infections, pathological fractures and hypercalcemia. All these are secondary to tumor-induced bone destruction through osteoclastic bone resorption. Bisphosphonates (BPs) are analogs of pyrophosphates that reduce bone resorption by inhibition of osteoclastic bone resorption and remodeling, and inhibition of angiogenesis. They are widely used for the management of multiple myeloma and bony metastases. [2] Osteonecrosis of jaws is a common complication of parenteral nitrogen-containing BPs, and medication-related osteonecrosis of the jaw (MRONJ) is osteonecrosis induced by anti-resorptive (denosumab) and anti-angiogenic medications. Patients may be considered to have MRONJ if there is a history of current or previous treatment with anti-resorptive or anti-angiogenic agents; exposed bone or bone that can be probed through an intraoral or extraoral fistula(e) in the maxillofacial region that has persisted for more than 8 weeks with no history of radiation therapy to the jaws or obvious metastatic disease to the jaws. [3] We report a case of multiple myeloma with osteolytic lesions in mandible that later developed MRONJ due to intravenous (IV) zoledronic acid after dental extraction.


   Case Report Top


A 70-year-old male patient reported to our outpatient department on June 13, 2015, with a chief complaint of nonhealing extraction site in relation to the left lower jaw for past almost 1 year. The patient was asymptomatic before August 2013 when he developed low back pain for which he consulted at a private hospital. He was advised magnetic resonance imaging (MRI) of thoracolumbar spine which revealed diffuse inhomogeneous marrow signals in spine and pelvic bones. Multiple T1-hypointense areas were seen in vertebral bodies suggestive of multiple myeloma or possible metastatic deposits. He was started on induction therapy with bortezomib and thalidomide in August 2013. Later, he developed symptoms of hypercalcemia (serum calcium: 14.6 mg/dl) and renal failure (serum creatinine: 5.2, blood urea: 104 and immunoglobulin G: 9096) in September 2013 following which chemotherapy was started with cyclophosphamide and IV zoledronic acid. He was under chemotherapy till October 2014, but stopped the treatment abruptly against medical advice due to financial constraints.

In January 2014, he developed pain and pus discharge in relation to mandibular left posterior tooth which was mobile for which he consulted at a private dental clinic where the offending tooth was removed. However, pain and pus discharge persisted. He again consulted at the hospital during his chemotherapy in April 2014 where orthopantomogram was taken and medications were advised. Later in June 2014, he underwent extraction of the adjacent tooth at the same hospital where he was under chemotherapy. Since then, he complains of an ulcer at the extraction site with intermittent episodes of pus discharge. Pus discharge was also present extraorally for past 3 months and the ulcerated area had gradually increased in size. He also complained of dull aching, intermittent, pain at the offending site for past almost 1 year which was relieved on medication, and feeling of numbness and tingling sensation in mandibular gingiva, chin and lower lip during the initial period of chemotherapy, but no such complaints were there at present. There was no other contributory medical, family and personal history. On general examination, the patient was moderately built and nourished with no signs of pallor, icterus, pedal edema, clubbing and cyanosis.

Extraorally, a small oval swelling measuring approximately 1 cm in largest diameter was seen, about 1 cm anterior to the left side angle of mandible. Skin overlying the swelling appeared shrunken, it had puckered edges probably due to scarring, and there was active serosanguineous discharge from the overlying sinus [Figure 1]. On palpation, it was soft to firm in consistency, smooth textured, slightly compressible, and tender with profuse discharge on digital pressure. No evidence of anesthesia or paresthesia was elicited on using cotton wisp test and blunt periodontal probe.
Figure 1: Skin overlying the swelling appeared shrunken, it had puckered edges probably due to scarring, and there was active serosanguineous discharge from the overlying sinus

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On intraoral examination, there was a mild restriction in opening mouth; the mouth opening was approximately 30 mm. Severe halitosis was present and oral hygiene was very poor with compromised periodontal status. An unhealed extraction socket was seen in the left posterior region of mandible covered with a pool of purulent fluid and an erythematous mucosal bulge was present along adnexal buccal mucosa. On cleaning with sterilized cotton gauze and normal saline solution, an unhealed extraction socket with exposed necrotic bone was seen. It was approximately 2.5 cm in diameter extending along the edentulous ridge in relation to 36, 37, and buccolingually, it was approximately 1 cm in width. On palpation, no expansion was felt along either cortex and there was no irregular or sharp margin. Severe tenderness was present. Mucosal bulge on buccal aspect was soft, compressible, and tender [Figure 2].
Figure 2: Unhealed extraction site, exposed necrotic bone, and mucosal bulge on buccal aspect was soft, compressible, and tender

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Routine hemogram, blood urea, serum creatinine and serum calcium were within normal limits, but serum immunoglobulin G was raised to 2529 IU. Mandibular left lateral oblique view did not reveal any expansion of buccal or lingual cortex. No periosteal reaction was seen. Sequential orthopantomograms revealed bony changes from osteolytic lesions of multiple myeloma to sequestrum formation at the time of presentation [Figure 3]a-d. Spiral contrast-enhanced computed tomography revealed an ill-defined hypodense area in the left side body of mandible with a central area of hyperdensity similar to cortical bone suggestive of a large sequestrum. Lingual cortex appeared thinned out and expanded compared to contralateral side [Figure 4]. MRI of the thoracolumbar spine revealed diffuse, inhomogeneous marrow signal in spinal column [Figure 5].
Figure 3: (a) Orthopantomogram as on April 4, 2014, revealed altered trabecular pattern in relation to edentulous 36 region with ill-defined areas of rarefaction. Few punched out lytic lesions were also seen in basal bone in relation to 31, 32, and 46 regions. (b) Orthopantomogram as on June 19, 2014, revealed an increased radio-opacity in relation to edentulous 36 region, the mixed radiolucent radio-opaque appears as moth-eaten suggestive of sequestrum. Multiple punched out radiolucencies were seen in mandibular basal bone. There was no evidence of thinning of the cortex or periosteal reaction. Inferior alveolar nerve canal appeared intact. (c) Orthopantomogram as on December 1, 2014 (postextraction of 37), revealed a further increase in radio-opacity in relation to edentulous 36, 37 area; the area is predominantly radio-opaque with radiolucent periphery. (d) Orthopantomogram as on June 13, 2015, revealed a mixed radio-opaque radiolucent lesion in relation to edentulous 36, 37 area with radio-opacity more than adjacent bone suggestive of sequestrum. No cortical discontinuity suggestive of pathologic fracture was seen

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Figure 4: Spiral contrast-enhanced computed tomography of mandible as on December 19, 2014, revealed an ill-defined hypodense area in relation to left side of mandible and a large sequestrum measuring approximately 21 mm × 15 mm reaching almost up to mandibular canal

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Figure 5: Magnetic resonance imaging of thoracolumbar spine as on August 16, 2013, revealed diffuse, inhomogeneous marrow signal in the spinal column and pelvic bone suggestive of multiple myeloma, and collapse compression of D12 vertebral body with associated marrow edema

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Based on history, clinical examination and radiographic findings, we arrived at a diagnosis of MRONJ. The patient was referred to the Regional Cancer Centre for further treatment of multiple myeloma. For oral complaints, the patient was advised symptomatic treatment with analgesics, reinforced oral hygiene maintenance with chlorhexidine 0.2% mouthwash, and antibiotic, amoxicillin 500 mg thrice daily for 1 week. The patient did not report back for further review.


   Discussion Top


Normal bone is a dynamic organ with a balance between bone formation from osteoblasts and resorption through osteoclasts. [4] Although there may be other mitigating factors, such as oral health, immune status, Karnofsky performance status or Kaplan-Feinstein index, BPs appear to be the necessary component in cases of MRONJ of jaw. [5] The risk for MRONJ among cancer patients enrolled in clinical trials and assigned to placebo groups ranges from 0% to 0.019%. [6] However, a recent study suggests that the prevalence of MRONJ is underestimated. [7] Among cancer patients exposed to zoledronate, the cumulative incidence of MRONJ is in the low single digits (range = 0.7-6.7%) which ranges between 50 and 100 times higher than cancer patients treated with placebo. [8] MRONJ is more likely to appear in the mandible (73%) than the maxilla (22.5%), but can appear in both jaws (4.5%). Dentoalveolar surgery is considered a major risk factor for developing MRONJ. Several studies report that among patients with MRONJ, tooth extraction is a common predisposing event ranging from 52% to 61% as in our case. In a longitudinal cohort study in a sample of cancer patients exposed to IV BPs (predominately zoledronate), tooth extraction was associated with a 33-fold increased risk for MRONJ. MRONJ appears to be time-dependent with higher risk after long-term use of BPs in older MM patients often after dental extractions similar to our patient. [9]

Diagnosis of medication-related osteonecrosis is clinical because it is preferable to avoid biopsy in patients taking BPs because of problems with healing postsurgical intervention. Hence, a biopsy is recommended only when there is a high clinical suspicion of metastasis. The diagnosis of osteonecrosis is, therefore, largely based on clinical criteria, with the key elements being an appropriate clinical presentation and BP use. As a result, radiology is likely to play an increasing role in confirming the diagnosis. [10] In the present case, sequential imaging reveals the initial punched out lytic lesions involving mandible and the bony changes following extraction of tooth despite being on zoledronate. The sclerotic changes were progressive, but did not encroach on the mandibular canal as in prior reported cases.

This case highlights the importance of radiographs and their meticulous interpretation in patients on BPs. If radiograph was properly interpreted at the onset, extraction should have been deferred or should have been done atraumatically under antibiotic prophylaxis, but ignorance on the part of general dentist probably worsened the situation. Alternate measures such as use of teriparatide and plasma-rich in growth factor have been found successful in the treatment of patients on BPs to restore the osteoblast/osteoclast homeostatic cycles through autologous cytokines. Moreover, this protocol reduces the risk of MRONJ when it is necessary to perform dental extractions in patients undergoing IV BP treatment. [11]


   Conclusion Top


Prevention and early identification of patients at risk of MRONJ should be of prime concern for all patients on BPs and meticulous interpretation of orthopantomograms in patients with malignancies and on BPs can be pivotal in identification of patients at risk of MRONJ.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
   References Top

1.
Rajkumar SV. Multiple myeloma. Curr Probl Cancer 2009;33:7-64.  Back to cited text no. 1
[PUBMED]    
2.
Cheng A, Mavrokokki A, Carter G, Stein B, Fazzalari NL, Wilson DF, et al. The dental implications of bisphosphonates and bone disease. Aust Dent J 2005;50 4 Suppl 2:S4-13.  Back to cited text no. 2
    
3.
Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, et al. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw-2014 update. J Oral Maxillofac Surg 2014;72:1938-56.  Back to cited text no. 3
    
4.
Tolar J, Teitelbaum SL, Orchard PJ. Osteopetrosis. N Engl J Med 2004;351:2839-49.  Back to cited text no. 4
    
5.
Hellstein JW, Marek CL. Bisphosphonate osteochemonecrosis (bis-phossy jaw): Is this phossy jaw of the 21 st century? J Oral Maxillofac Surg 2005;63:682-9.  Back to cited text no. 5
    
6.
Coleman R, Woodward E, Brown J, Cameron D, Bell R, Dodwell D, et al. Safety of zoledronic acid and incidence of osteonecrosis of the jaw (ONJ) during adjuvant therapy in a randomised phase III trial (AZURE: BIG 01-04) for women with stage II/III breast cancer. Breast Cancer Res Treat 2011;127:429-38.  Back to cited text no. 6
    
7.
Walter C, Al-Nawas B, Frickhofen N, Gamm H, Beck J, Reinsch L, et al. Prevalence of bisphosphonate associated osteonecrosis of the jaws in multiple myeloma patients. Head Face Med 2010;6:11.  Back to cited text no. 7
    
8.
Vahtsevanos K, Kyrgidis A, Verrou E, Katodritou E, Triaridis S, Andreadis CG, et al. Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw. J Clin Oncol 2009;27:5356-62.  Back to cited text no. 8
    
9.
Badros A, Weikel D, Salama A, Goloubeva O, Schneider A, Rapoport A, et al. Osteonecrosis of the jaw in multiple myeloma patients: Clinical features and risk factors. J Clin Oncol 2006;24:945-52.  Back to cited text no. 9
    
10.
Novartis. Expert panel recommendation for the prevention, diagnosis and treatment of osteonecrosis of the jaw. East Hanover, NJ: Novartis; 2005.  Back to cited text no. 10
    
11.
Mozzati M, Arata V, Gallesio G. Tooth extraction in patients on zoledronic acid therapy. Oral Oncol 2012;48:817-21.  Back to cited text no. 11
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]



 

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