OSTEONECROSIS OF THE LOWER JAW, ASSOCIATED WITH THE APPLICATION OF ORAL BISPHOSPHONATES CASE REPORT

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1 OSTEONECROSIS OF THE LOWER JAW, ASSOCIATED WITH THE APPLICATION OF ORAL BISPHOSPHONATES CASE REPORT P. Pechalova 1, A. Bakardjiev 2, B. Vladimirov 1, E. Poriazova 3, Z. Zaprianov 3, I. Angelova 4, A. Zheleva 1 1 Department of Maxillofacial Surgery, Faculty of Dental Medicine, Medical University - Plovdiv 2 Department of Oral Surgery, Faculty of Dental Medicine, Medical University Plovdiv 3 Department of General and Clinical Pathology, Medical University Plovdiv 4 Department of Imaging Diagnostics, Physiotherapy and Allergology, Faculty of Dental Medicine, Medical University Plovdiv J Clin Med. 2009; 2(2):59-64 Key words: Bisphosphonate associated osteonecrosis, Alendronate, Ibadronate, osteoporosis Adress for correspondence: P. Pechalova, M.D., Department of Maxillofacial Surgery, Faculty of Dental Medicine, Medical University Plovdiv, 66 Peshtersko Shose Blvd, 4 th floor, pechalova@abv.bg Abstract: The authors present a case of subclinical osteonecrosis of the lower jaw (mandible), associated with oral application of Fosamax R (Alendronate), 70 mg weekly dose, and Bonviva R (Ibadronate), 150 mg monthly dose, for 28 months, preceded by insertion of new complete dentures in a 80-year-old female patient with severe osteoporosis. The osteonecrosis has been initially discovered through CT scan and pathohistologically confirmed after necrectomy. jaws in patients receiving bisphosphonates Case report 42. In 2005, Novartis (the manufacturer of Aredia and Zometa 48 ) officially declared 475 cases of Bisphosphonate In the last six years numerous publications can be associated osteonecrosis of the jaws (BAOJ) 17. found on a new type of complication, associated Presently, different authors keep on reporting cases with the application of Bisphosphonates avascular on bisphosphonate associated osteonecrosis of the osteonecrosis of the jaws, defined as a necrosis. It is jaws 5,24,28,33,35,43,44, therefore the actual number of the related or not to dental procedures, and persists for cases worldwide remains unknown. The frequency of more than 6 to 8 weeks. It is resistant to conservative bisphosphonate associated osteonecrosis of the jaws treatment. It is presented in patients without history of according to the official publications is between 1.3% 9 preceding radiotherapy in the affected area, but who and 10% 6. have been treated with amino-acid bisphosphonates - intravenously for at least one year, or orally for a much More than 2.5 million patients are treated with longer period of time, on the occasion of a common bisphosphonates 46. Nearly 2 million people receive disease occurring with bone resorption 1. bisphosphonates as part of their anti-tumour therapy 17. The number of patients on oral bisphosphonates In 2003, Marx first published 36 cases of painful because of osteoporosis is constantly increasing. In refractory bone exposures of the mandible and the USA 10 million people (7.8 million women and maxilla in patients treated with the bisphosphonates 2.3 million men) suffer from osteoporosis and the pamidronate and zoledronate 32. The same year, prognosis is that until 2010 their number will increase Migliorati reported five cases 36, Carter and Gross up to 12 million million people over 50 years of four 12, Wang three 47. One year later, Ruggiero et al. age have got reduced bone mass, which puts them in published a review of 63 cases of osteonecrosis of the risk of developing the disease 10. Bisphosphonates are 59

2 Bisphosphonate Associated Osteonecrosis of Lower Jaw the preferred drugs in the treatment of osteoporosis. In 2003 in the USA, oral bisphosphonates have been prescribed in 73% of the 6.3 million patient visits on grounds of osteoporosis. More than 190 million prescriptions for oral bisphosphonates have been administered worldwide 2. In 2003, Alendronate was the 19 th most frequently prescribed medicine (17 million prescriptions), Risendornate was the 72 nd with 6 million prescriptions, while Zolendronate was administered to more than patients 6,30. Until now, no evidence based therapeutic strategy has been developed for the treatment of BAOJ and the condition has been accepted as irreversible. Therefore, all the efforts of the medical scientific community have been focused on preventing it 3,23,25,34,38,48. The purpose of this report is to present the first Bulgarian case of subclinical bisphosphonates associated osteonecrosis of the mandible in a patient treated with oral bisphosphonates because of severe osteoporosis. Case report The case follows an 80-year-old female patient, who had been treated for 14 months consistently with Fosamax R (Alendronate), 70 mg orally once Picture 1. per week, and Bonviva R (Ibadronate), 150 mg orally CT scan of the mandible once per month, because of severe osteoporosis with pathologic fractures of vertebral bodies (T-Score = -2.8). Eight months before the clinical examination and 20 months after the start of the bisphosphonate therapy, complete dentures had been implanted in patient s oral cavity. After the procedure, she started complaining from recurrent, painful swellings in the right part of the lower jaw, resistant to antibiotic treatment. After numerous consultations with dental doctors and oral surgeons, she was appointed for a consultation with a maxillofacial surgeon. The physical status revealed mucosal hyperaemia of the distal segment of the mandibular vestibule on the right, without exposure of the bone and a presence of an active inflammation, provoking a strong palpation pain. Extra-orally, there was a slight perimandibular oedema, without fluctuation, painful when palpated. The laboratory tests didn t show any deviations from the normal referent values. We performed a native CT scan of the mandible with a 2mm section thickness, which confirmed the osteoporotic structure of the bone with cellular and pseudo-cystic changes, as well as the presence of a massive oedema of the premolar and molar soft tissues on the right and lysis of the vestibular cortex lamella and the underlying spongiosa with a formation of a thick bone segment in the area of the oedema (picture 1). Using local anaesthesia, we raised a mucoperiostal flap in the area of the premolars and molars on the right, uncovered the bone surface, which revealed its porous structure and chalk white colour (picture 2) and removed the macroscopically obvious transformed bone, which was sent for pathohistological examination. The result presented a bone tissue with a necrosis and non-exuberant leucocytes infiltration (picture 3). The wound healed by primary closure. The patient was administered a 14-day intravenous application of Penicillin ( UI every 6 hours), followed by a 30-day course of Ospen 1500 (1 tablet every 8 hours). The pains disappeared. Since then, the patient has been on regular follow up examinations and once mentioned that the observing endocrinologist recommended ceasing the bisphosphonate therapy. 60

3 J Clin Med. 2009; 2(2):59-64 Discussion The bisphosphonates discovered in the late 60 s of the XX century, are a synthetic analogue of the nonorganic pyrophosphates, with a powerful inhibiting effect over the osteoclastic activity. They incorporate in the skeletal bones without being metabolized 28. The bisphosphonates attach to Ca 2+ in the zones of high bone resorption and remain integrated into the bone for more than 10 years 40 the halflife of Alendronate for example is 12 years 28. Once taken, the bisphosphonates unlock a cascade of biochemical reactions, leading to loss of osteoclasts ability to resorb bone or even to their apoptosis 7,11. They are administered in the treatment of diseases, characterized with high grade of bone resorption multiple myeloma, osteolytic bone metastases, Paget s disease of the bone 17, fibrous dysplasia 13,14,27, McCune Albright syndrome, hypercalcaemia with neoplastic origin, osteoporosis. BAOJ comes as a result of the expected postbisphosphonate therapy suppression of the bone metabolism and the accumulation of physiological micro-lesions of the jaw bones, thus compromising their biomechanical properties. The trauma and infection increase the necessity of adequate bone regeneration which exceeds the recovery capacity of the hypo-dynamic bone, so in result a local osteonecrosis develops. Sook Bin Woo et al. accept that bisphosphonate associated osteonecrosis appears only in the jaw bones because they are not as protected as the other bones in the body. This is supported by the fact that they are kept from eventual intra-oral trauma only by the thin mucosa and periost. In addition, the presence of teeth in the jaws may facilitate the penetration of microorganisms and the development of inside bone infection through complications of dental caries and parodontopathy 48. According to Danneman et al. 17, all the cases of osteonecrosis of the jaws described until 2006, are related entirely to the application of amino-acid bisphosphonates. In the scientific literature there is no common accord on which amino-acid bisphosphonates more frequently cause the development of BAOJ, although most of the research evidences stand for the predominant opinion that the use of Zoledronic Picture 2. Intraoperative finding accompanying the osteonecrosis of the mandible Picture 3. Pathohistological sample of the osteonecrosis of the mandible hematoxylin-eosin staining acid is the most risky 6,15,16,19. Most of the cases with BAOJ are related to intravenous application of bisphosphonates 17. Until now, only 26 cases of BAOJ related to oral application of bisphosphonates have been published worldwide 39. Their analysis shows that the condition affects mostly the mandible (16 cases); 78% of the patients (18 people) are over 60 years of age and only 13% (3) of them are men. Sook Bin Woo et al. report that only 6% of the patients with BAOJ have been treated with oral bisphosphonates because of osteoporosis or Paget s disease of the bone

4 Bisphosphonate Associated Osteonecrosis of Lower Jaw Bamias A. et al. suggest that there is a strong relationship between the duration of the bisphosphonate treatment and the development of jaw necrosis 6. The collected data on the development of BAOJ indicate duration of oral bisphosphonate application between 12 and 72 months 39. In the literature predominant remain the reports of BAOJ development with preceding dental manipulations, compared to the so called spontaneous BAOJ 3,4,6,7,8,11,13. Between 33% and 86% of the reported BAOJ cases manifested after various dental procedures 48. There is also a suggestion that every age decade increases by 9% the risk of developing BAOJ 4. discovered in its subclinical state CT data for necrosis without clinical exposure of the bone, but with pathohistological confirmation. This case report contributes to the knowledge of bisphosphonates side effects and reveals the opportunities for BAOJ prevention among the patients with osteoporosis, treated with bisphosphonates. Conflict of Interest The authors declare lack of circumstances and full disclosure about conflict of any interest that may arise from writing this article There is no consensus on the necessity of ceasing bisphosphonates therapy whenever a BAOJ is diagnosed. Marx suggests consulting bisphosphonate therapy of cancer patients with an oncologist in order to evaluate the risk/benefit ratio 31, considering the long half-life (10 years) of bisphosphonates. Other authors share the same opinion 21,37, while Dunstan et al. stand for stopping bisphosphonate treatment 18. A therapeutic method of choice that most authors recommend avoiding 36,42 because of the danger of involving new bone tissues, is necrectomy and plastic surgery with a mucoperiostal flap. However, we do recommend it in cases of not too large necrosis and when there are sufficient surrounding soft tissues. Graziani et al. 22 propose a therapeutic scheme, including antibiotic treatment and alternate debridement for removing the necrotic tissues and reduction of the symptoms, without excluding the opportunity for occasional sequesterectomy and resection if needed. A common opinion in the literature is that aggressive surgical behaviour is counterproductive and leads to worsening of the condition, therefore is to be avoided 18,31,36,42. Nastro et al. emphasize that antibiotics cannot penetrate the necrotic tissues and are used only for influencing cellulitis in the adjacent tissues 37. Conclusion The present review reports the first case of osteonecrosis of the jaws in Bulgaria associated with oral application of Alendronate (Fosamax R ) and Ibadronate (Bonviva R ). The condition was 62

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