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Authors:Dr. Aruna Tambuwala,Dr. Deepak Kaul,Dr. Ajinkya Vyawahare.

Abstract
Bisphosphonates are frequently used for the treatment of bone metastases, multiple myeloma, osteoporosis and other bone diseases. Generally these drugs are well tolerated, rarely inducing clinically significant side effects. However, recent reports have described osteonecrosis of the jaw bones (ONJ) as a potentially serious complication related to the long-term use of these drugs. Here we present a case which were diagnosed and treated for bisphosphonate related osteonecrosis of  jaw with good long term outcome.

Introduction
Bisphosphonates are frequently used for the treatment of bone metastases, multiple myeloma, osteoporosis and other bony diseases. Generally these drugs are well tolerated, rarely inducing clinically significant side effects such as gastrointestinal symptoms for oral bisphosphonates, elevated serum creatinine, transient low-grade fever, arthralgias and increased bone pain for the injectable drugs. However, recent reports have described osteonecrosis of the jaw bones (ONJ) as a potentially serious complication related to the long-term use of these drugs. 1-3 Since the first reports in the literature of bisphosphonate- related osteonecrosis of the jaw (BRONJ), the medical and dental communities have been investigating the pathogenesis and treatment of this condition.4-5 This condition, termed bisphosphonate- related osteonecrosis (BRON), has been increasingly recognized. The clinical entity of BRON is similar to elemental phosphorus necrosis of the jaw reported over a century ago.6 Initially, BRON was seen only with the use of the more potent intravenous forms of the drug; however, there have been reports of osteonecrosis in patients who are taking the less potent oral forms also.7-9 Although found in both sexes, the literature reports more cases of BRON in women than men, which is likely a reflection of the large number of cases reported in patients who have breast cancer. With postmenopausal osteoporosis as an indication for bisphosphonate use, a large percentage of the female population also may be at risk for developing BRON10.

CASE REPORT
72yrs old female reported to Dept. of oral and maxillofacial surgery with chief complaint of history of extraoral swelling in the left submandibular region of jaw since 1 year. The patient had a history of multiple myeloma for which she was treated with intravenous zoledronic acid (inj zometa 4mg/iv Novartis) supplemented with Melphalan 6mg and Prednisolone (Tab. Wysolone 20mg, ) 4 years back. General condition of the patient was good. Patient was hypertensive from past 7-8 years and was on regular treatment for the same with Tab. Bisoprolol fumarate (Tab. Bisolol ).

 

     
1. front profile 2. Extraoral draining sinus 3. intraoral draining sinus

Extra-oral examination of the involved area revealed a sinus formation in the left submandibular region. There was occasional pus discharge associated with the sinus. Left submandibular lymph nodes were hard, and tender on palpation. Intraoral examination revealed completely edentulous maxillary and mandibular arches. Examination revealed sinus formation in the left premolar-molar region.

 

     
4. 3d CT 5. curratage of lesion 6. 1 week follow up

Treatment planned and executed was excision of the lesion which included through debridement followed by curettage along with sequestrectomy. Surgical treatment was supported medically by intravenous antibiotics which included inj. Cefotaxime 1gm (inj taxim 1gm/iv, Alkem ) and inj Metronidazole 100ml(inj flagyl 100ml/iv, Baxter).

   
7. 1 year follow up 8.follow up

Patient was reviewed at regular intervals that is at 1 month, 3 monts and 6 months and 1 year. Patient did not show any sign of recurrence of the lesion and no other complaints was reported.

Review
• Bisphosphonates:
These are currently the major class of drugs used for the treatment of osteoporosis and other diseases characterized by increased bone resorption (e.g. metastatic bone disease, and Paget’s disease)11. They are also used to manage patients with multiple myeloma and hypercalcemia10. Structurally, bisphosphonates resemble the endogenous molecule pyrophosphate. However, bisphosphonates possess a central carbon atom linking 2 phosphate groups instead of a central oxygen atom, which links the phosphate groups in the endogenous pyrophosphate13. Bisphosphonates can be administered orally or intravenously. Regardless the type of bisphosphonate, after administration a high portion will be cleared non-metabolized from the body within a few hours through the urine11. Bisphosphonates are potent inhibitors of osteoclastic activity. They are readily deposited in bone and remain within the bone mass for years. Bisphosphonates are internalized by osteoclasts and subsequently disrupt osteoclastic-mediated bone resorption14-16. Bisphosphonates can be divided into two pharmacologic groups: the nitrogen-containing bisphosphonates and the non-nitrogen containing bisphosphonates. Nitrogen-containing bisphosphonates inhibit farnesyl disphosphate synthase (FPP synthase): an enzyme active in the mevalonate pathway. This FPP synthase inhibition in osteoclasts results in a reduced bone resorption through different dose dependent ways17. The non-nitrogen containing bisphosphonates promote osteoclast apoptosis due to their conversion into methylene-containing adenosine triphosphate analogues. Ths inhibits critical adenosine triphosphate-dependent enzymes, particularly and signifiantly, the adenine nucleotide translocase of the mitochondrial transition pore complex, which is an important trigger causing apoptosis18.
Bisphosphonates and osteonecrosis of jaws
o Epidemology: The risk of developing osteonecrosis of the jaw, whilst receiving bisphosphonates, varies between 1 and 10%7. Approximately 94% of all bisphosphonate users who develop BRONJ are using Pamidronate, Zolendronate or both19. It has also been shown that intravenous bisphosphonate therapy (Zolendronate, Pamidronate) is of greater risk to develop BRONJ, compared to oral application of bisphosphonates20,21. However, oral bisphosphonate users are not excluded entirely from developing BRONJ. Patients receiving bisphosphonates orally during three years or more are considered to be at high risk7.. Besides this, there is also another intervention highly related to BRONJ. 60% of all BRONJ occurred after a (dental) surgical procedure. In most cases (53.8%), BRONJ developed following tooth extraction or minor surgical interventions. Placement of dental implants is also frequently related to BRONJ21.
o Current Hypothesis
Several views have been put forward to offer a possible explanation for the occurrence of BRONJ. Tubiana-Hulin et al21. assumed, a general decrease in bone remodeling being responsible for BRONJ . This can be attributed to high bone remodeling rate of the jaws, which ten to twenty times higher than remodeling rate of the cortex of the iliac crest23. Another hypothesis is based on the fact that some reports indicate that Zolendronate and Pamidronate have an anti-angiogenic activity (the ability of bisphosphonates to inhibit vascular endothelial growth factor and formation of new capillaries), whichcan predispose certain bone sites to the development of avascular necrosis. This might be a plausible explanation for the favorable location of osteonecrosis, being the jaws. Several authors suggest that the jaws are poorly vascularised, resulting in poor wound healing and osteonecrosis. However, the only data available concerning mandible blood flow shows values for the mandible that are similar to those for long bones23. These findings thus appear to contradict each other and therefore do not entirely explain the favorable location for the jaws.
o Clinical features:
BRONJ is seen in patients receiving or having received bisphosphonates as an area of exposed bone in the maxillofacial region that does not heal within 8 weeks7. The early clinical symptoms include non-healing ulceration, pain, and where present loosening of teeth, features of infection such as swelling, erythema and a discharging sinus. In advanced disease, exposed necrotic bone will be present and in the most severe conditions pathologic fracture, extra-oral fistula and oral antral/oral nasal communication may be present5. The clinical staging of BRONJ according to Chaudhry et al.10 (table 1) is based on the the degree of bone exposure and clinical symptoms. Radiologic diagnosis is needed to determine the severity of the affected bone. However, in early stages there may be no obvious radiological changes. At a later stage there will be evidence of bone motting and sequester formation, similar to osteomyelitis12.
o Treatment:
The primary treatment of BRONJ aims mainly towards preventing necrosis of jaws, which mainly deals with elimination of any active or potential infective focus before starting the therapy. Secondly, treatment of patients with ongoing BRONJ therapy depends upon the nature, severity and clinical presentation of the lesion. The treatment is summarized in (table 2).


Conclusion:
Bisphosphonates may cause osteonecrosis of jaws in cases of active therapy and even after stoppage of therapy. In our case, BRONJ was seen due to constant denture irritation after 3 years of cessation of bisphosphonate therapy. Thus osteonecrosis after stoppage of therapy must be speculated. To our conclusion, surgical excision and curettage of the lesion which is then supported medically with intravenous antibiotics shows good resolution of lesion with good long term treatment outcome.

REFERENCES
 

  1. Carter G, Goss AN, Doecke C. Bisphosphonates and avascular necrosis of the jaw: a possible association. Med J Aust 2005;182(8):413–5.
  2. Drake MT, Clarke BL, Khosla S. Bisphosphonates: mechanism of action in clinical practise. Mayo Clin Proc 2008;83(9):1032–45.
  3. Greenberg MS. Intravenous bisphosphonates and osteonecrosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004;98(3):259–60.
  4.  Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced Avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003;61:1115-7.
  5.  Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004;62:527-34.
  6. Hellstein JW, Marek CL. Bisphosphonate osteonecrosis (bis-phossy jaw): is this phossy  jaw of the 21st century? J Oral Maxillofac Surg 2005;63:682–9.
  7. Khosla S, Burr D, Cauley J, et al. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2007;22:1479-91.
  8. Ruggiero S, Woo V, Mehrotra B, et al. Osteonecrosis of the jaws associated with the use of bisphosphonate medications: a report of 60 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004;98:196–7.
  9. Hellstein JW. Osteonecrosis warning: cancer drugs preclude some dental  procedures. American Dental Association News, May 16, 2005;12.
  10. Chaudhry N A, Ruggiero SL. Osteonecrosis and Bisphosphonates in Oral and Maxillofacial Surgery. Oral Maxillofacial Surg Clin N Am 19 (2007) 199- 206.

More references are available on request

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