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| IMAGE CHALLENGE |
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| Year : 2020 | Volume
: 3
| Issue : 1 | Page : 93-96 |
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The mystery of the jaw pain
Madhuri Waghmare, Ankita Ahuja, Pooja Pande, Abhishek Mahajan
Department of Radio-Diagnosis, Tata Memorial Hospital, Mumbai, Maharashtra, India
| Date of Submission | 21-Sep-2019 |
| Date of Decision | 16-Oct-2019 |
| Date of Acceptance | 14-Nov-2019 |
| Date of Web Publication | 24-Feb-2020 |
Correspondence Address:
Madhuri Waghmare
Room No 701, Zeon B, Ajmera I-Land, Near Bhakti Park, Wadala, Mumbai, Maharashtra
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/CRST.CRST_66_19
How to cite this article:
Waghmare M, Ahuja A, Pande P, Mahajan A. The mystery of the jaw pain. Cancer Res Stat Treat 2020;3:93-6 |
| Case History | |  |
A 74-year-old female was diagnosed with breast carcinoma with vertebral metastasis and malignant pleural effusion. She was started on endocrine therapy with fulvestrant, letrozole, and zolendronate, as the cancer was strongly hormone receptor positive. She also received radiation to the vertebral metastasis from 2013 to 2014. In February 2017, she presented with back pain for which magnetic resonance imaging (MRI) was performed which revealed degenerative changes without new metastatic lesion. She received an epidural steroid injection for this. The patient continued the above-mentioned systemic therapy and was on 3-month follow-up with routine laboratory investigations including renal function test. In July 2019, she presented with jaw pain, and on oral examination, no obvious abnormality was detected. On further clinical questioning, she revealed that she had undergone tooth extraction in June 2019. An orthopantomaogram (OPG) was performed [Figure 1]. MRI and CT of the jaw were performed [Figure 2] and [Figure 3]. What could be the possible cause for her pain and the clinical diagnosis? Once you have finalized your answer, please turn to pg. 94 and read on. | Figure 1: Orthopantomogram shows an irregular lytic sclerotic area in the left body and ramus of the mandible
Click here to view |
 | Figure 2: (a) Coronal short-tau inversion recovery image showing hyperintense signal along both the inner–outer cortices of the mandible (arrow), (b and c) coronal and axial postcontrast images demonstrate similar high-intensity signal along both the cortices of the left hemimandible
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 | Figure 3: Computed tomography sections of the mandible in bone algorithm (a). Axial computed tomography shows moth-eaten and permeative destruction of the left hemimandible (b and c). Coronal and oblique reformat demonstrate a similar destructive pattern as seen in the axial section
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| Workup and Management | | |
The OPG revealed an ill-defined irregular lytic sclerotic area in the left body and ramus of the mandible. For furthur charaterization, MRI of the jaw was performed [Figure 2], which showed short-tau inversion recovery hyperintensity and T2 intermediate signal along both the internal and external cortices of the left body and ramus of the mandible. The involved segment was hypointense on T1 and showed intense postcontrast enhancement more so on the left side as compared to the right.
Additional limited computed tomography (CT) was done to look at the extent of bone erosion [Figure 3]. It showed a moth-eaten as well as permeative type of bone destruction involving the left hemimandible and the inferior alveolar canal.
Radiological differentials included osteonecrosis, chronic osteomyelitis, and metastasis; however, considering the history of bisphosphonate intake, the diagnosis of bisphosphonate-induced osteonecrosis was made.
Zoledronate was withheld, and the patient was started on denosumab instead. She received hyperbaric oxygen therapy, along with antibiotics and was asked to use oxum spray on a regular basis and to follow-up in the dental OPD for the ostenecrosis.
| Discussion | | |
Normal bone is a dynamic organ in which equilibrium is maintained between the bone formation by osteoblasts and bone resorption by osteoclasts.[1] Bisphosphonates are the inorganic pyrophosphates that decrease the bone resorption by inhibiting the osteoclasts, therefore decreasing the overall bone turnover. This results in modifications in the bone and predisposes it to microdamage, with jaws being particularly susceptible due to their high turnover. Bisphosphonates are metabolically inactive and they bind to the bone, creating a reservoir that remains even after discontinuation of the treatment.[2],[3]
The first-generation bisphosphonates are clodronate and etidronate, which are oral agents and act by inducing apoptosis of the osteoclasts. The newer nitrogen-containing drugs are given intravenously, have high potency, and inhibit the osteoclasts by acting on the enzyme in the cholesterol biosynthetic pathway called farnesyl diphosphate synthase. In oncology, bisphosphonates are used in lytic bone metastases, multiple myeloma, hypercalcemia of malignant origin, osteoporosis, and diseases such as Paget's, providing significant improvement in the symptoms by reducing the pain, bone demineralization, and bone fractures either pathological or due to bone insufficiency.[3],[4]
The short-term adverse effects of bisphosphonates include upper gastrointestinal intolerance due to oral administration of these drugs, severe musculoskeletal pain, and acute-phase reaction characterized by fever, following the first infusion of intravenous bisphosphonates, ocular inflammation such as uveitis, conjunctivitis, scleritis, and transient hypocalcemia with secondary hyperparathyroidism. Hypocalcemia as an adverse effect is more marked in patients with hypoparathyroidism, impaired renal function, hypovitaminosis D, limited calcium intake, or high rates of osteoclast-mediated bone resorption such as seen in Paget's disease of the bone or in a case of large skeletal tumor burden. The long-term adverse effects include severe suppression of bone turnover, subtrochanteric femur fractures, and osteonecrosis of the jaw (ONJ).[5] Bisphosphonate-related ONJ (BRONJ) was first described by Marx in 2003, Migliorati, and Pogrel.[4]
The prevalence of ONJ is variable and has been reported to be 1%–10% in patients receiving intravenous bisphosphonate treatment for cancer. Two-third of the cases involve the mandible, one-fourth involve the maxilla, and the remaining cases involve both the bones.[1] The estimated risk for oral bisphosphonate use remains uncertain, but the occurrence appears to range from 1 in 10,000 to 1 in 100,000 patient-years. The mandible is the most commonly affected bone, as it is the site of maximum turnover and bone remodeling secondary to the occlusal forces acting on it.
Based on the mechanism of action of bisphosphonates and the occurrence of ONJ in association with bisphosphonate use, few theories have been presumed. The first is the metabolic theory which is based on the altered balance between the osteoclasts and osteoblasts, an effect which is similar to that seen in osteopetrosis, wherein there is a defect in bone resorption by osteoclasts.[3] The other postulated one is the antivascular theory which is based on the antiangiogenic effects of bisphosphonates. The third is the Wolff's law which states that bone remodeling takes place secondary to the forces applied to it. As the mandible and maxilla are subjected to strong occlusal forces transmitted by teeth and periodontal ligaments, there is a high bone turnover which predisposes the jaw to certain conditions.[3]
There is an increased risk of developing BRONJ in patients who receive intravenous nitrogen-containing bisphosphonates such as zoledronate and pamidronate. The occurrence of BRONJ is related to cumulative dose, type of drug used, dosage, duration of therapy, and nitrogen-containing bisphosphonates. The cumulative hazard of developing BRONJ is significantly higher with zoledronate treatment due to its more potent inhibitory effect on the bone turnover rate and its antiresorptive properties. Intravenous zoledronate benefits in the long-term management of bone metastasis as it requires less frequent administration and thus better compatibility as compared to oral drugs which require frequent administration and have a poor bioavailability, and compliance, thus, was used in our patient.
The diagnosis of this condition is primarily clinical. Imaging helps in identifying early lesions in high-risk patients which may have favorable implications in terms of clinical outcome.[1] CT and MRI are indeed superior to panoramic radiography in delineating the margins of the lytic lesions, identifying the extent of the disease, better spatial resolution, sclerosis, and periosteal reaction. It also provides information about the involvement of the paranasal sinuses, the mandibular canal, locoregional adenopathy, and even identifying the multiplicity and location of focal lesions. MRI also gives an excellent contrast detail of the soft tissue and marrow involvement.[6]
The management includes discontinuation of the bisphosphonates; however, the definite strategies are yet to be established.[7] Several medical and surgical treatment protocols have been proposed, but there is no general consensus as to what the initial management needs to be. The treatment options include minimally invasive surgeries, wherein sequestrectomy, curettage, debridement, or smoothening of the bone are done; CT and MRI help in deciding the extent. Medical management includes the use of various growth factors to promote soft- and hard-tissue healing. The ozone therapy and hyperbaric oxygen therapy have been reported to be effective adjunctive therapies. The ozone acts by stimulating the endogenous antioxidant system, increases the number of red blood cells, and enhances diapedesis and phagocytosis. The hyperbaric oxygen therapy generates reactive oxygen species and reactive nitrogen species which affects the signaling process critical to wound healing and it aids in angiogenesis, which leads to increased oxygen concentration and antibiotic levels in patients with ONJ.[7]
Differential diagnosis
The radiological differential diagnosis for bisphosphonate- associated osteonecrosis includes:
- Chronic sclerosing osteomyelitis of the mandible reveals periosteal new bone formation, sclerosis, osseous expansion, and sequestra[3],[8]
- Osteoradionecrosis follows radiation therapy to the oral cavity and radiologically manifests as poorly defined destruction of the mandible[3],[9]
- Metastases to the jaw are uncommon, and the posterior mandible is the most commonly involved site, with mandible lytic lesions being frequent; however, in breast and prostate cancer metastases, they may be sclerotic[3]
- Paget disease typically manifests by osseous expansion and coarsened trabeculae.[3]
| Conclusion | | |
The diagnosis of osteonecrosis is primarily clinical; however, the clinical presentation is not typical and mimics other conditions such as osteomyelitis, osteoradionecrosis, or neoplastic involvement of the bone. The primary role of imaging is to demonstrate the extent of disease prior to any surgical intervention and to detect complications such as a pathological fracture.[1] It is crucial to consider ONJ as a differential diagnosis in patients with a history of bisphosphonate treatment to avoid unwarranted biopsies with potentially hazardous outcomes.[1]
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
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| 2. | Haworth AE, Webb J. Skeletal complications of bisphosphonate use: what the radiologist should know. Br J Radiol 2012;85:1333-42. |
| 3. | Phal PM, Myall RW, Assael LA, Weissman JL. Imaging findings of bisphosphonate-associated osteonecrosis of the jaws. AJNR Am J Neuroradiol 2007;28:1139-45. |
| 4. | García-Ferrer L, Bagán JV, Martínez-Sanjuan V, Hernandez-Bazan S, García R, Jiménez-Soriano Y, et al. MRI of mandibular osteonecrosis secondary to bisphosphonates. AJR Am J Roentgenol 2008;190:949-55. |
| 5. | Kennel KA, Drake MT. Adverse effects of bisphosphonates: Implications for osteoporosis management. Mayo Clin Proc 2009;84:632-7. |
| 6. | Koth VS, Figueiredo MA, Salum FG, Cherubini K. Bisphosphonate-related osteonecrosis of the jaw: From the sine qua non condition of bone exposure to a non-exposed BRONJ entity. Dentomaxillofac Radiol 2016;45:20160049. |
| 7. | Fliefel R, Tröltzsch M, Kühnisch J, Ehrenfeld M, Otto S. Treatment strategies and outcomes of bisphosphonate-related osteonecrosis of the jaw (BRONJ) with characterization of patients: A systematic review. Int J Oral Maxillofac Surg 2015;44:568-85. |
| 8. | Suei Y, Taguchi A, Tanimoto K. Diagnosis and classification of mandibular osteomyelitis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;100:207-14. |
| 9. | Deshpande SS, Thakur MH, Dholam K, Mahajan A, Arya S, Juvekar S. Osteoradionecrosis of the mandible: Through a radiologist's eyes. Clin Radiol 2015;70:197-205. |
[Figure 1], [Figure 2], [Figure 3]
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