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Bisphosphonates and avascular necrosis of the mandible: Case report and review of the literature
Journal of Plastic, Reconstructive & Aesthetic Surgery (2008) 61, 94e98
CASE REPORT
Bisphosphonates and avascular necrosis of the mandible: Case report and review of the literature Dylan J. Murray a,b, Martin J.J. Vesely a,b, Christine B. Novak b, Jonathan Irish b,c, Michael Crump d, Peter C. Neligan a,b,* a
Division of Plastic Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada b Wharton Head & Neck Centre, University Health Network, Toronto, Ontario, Canada c Department of Otolaryngology e Head & Neck Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada d Department of Medical Oncology & Hematology, University Health Network, University of Toronto, Toronto, Ontario, Canada Received 8 May 2006; accepted 6 June 2006
KEYWORDS Bisphosphonates; Avascular necrosis; Cancer; Head and neck; Case report
Summary Background: Avascular necrosis of the mandible or maxilla is being recognized with increasing frequency in patients who are being treated with bisphosphonates for metastatic cancers. Methods and results: A patient who was treated for avascular necrosis following treatment with bisphosphonates for multiple myeloma is presented. Conclusion: Prophylactic and preventative measures should be instituted prior to commencing treatment with bisphosphonates to minimize the risk of developing avascular necrosis. ª 2006 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
Avascular necrosis of the mandible or maxilla has been recognized with increasing frequency in patients who were being treated with bisphosphonates * Corresponding author. Division of Plastic Surgery, Toronto General Hospital, 8N-865 200 Elizabeth Street, Toronto, ON M5G 2C4, Canada. Tel.: þ1 416 340 3449; fax: þ1 416 340 4403. E-mail address: [email protected] (P.C. Neligan).
for metastatic cancers.1e8 A patient who was treated for avascular necrosis following the treatment with bisphosphonates for multiple myeloma is presented. A number of prophylactic and preventative measures should be followed prior to a patient commencing treatment with bisphosphonates to minimize the risk of developing avascular necrosis.
1748-6815/$ - see front matter ª2006BritishAssociationofPlastic,ReconstructiveandAestheticSurgeons.PublishedbyElsevierLtd.Allrightsreserved. doi:10.1016/j.bjps.2006.06.017
Bisphosphonates and avascular necrosis
95
Case report A 60-year-old male presented initially with a lytic scalp lesion and hypocalcaemia. In February 2000, the patient was diagnosed with IgA multiple myeloma. His past social/medical history included alcoholism, hypertension and chronic obstructive airway disease as well as a silent myocardial infarct some years previously. His medical comorbidity precluded stem cell transplantation and he was commenced on standard melphan and prednisone and pamidronate to treat the lytic scalp lesion and the hypocalcaemia. Within a year, he was found to be resistant to the melphan/prednisone combination and was treated with weekly cylophosphamide and alternate day prednisone. This was complicated by severe hyperglycaemia. In April 2002, because of disease progression he began decadron 40 mg daily every 2 weeks combined with thalidomide 200 mg/day. Eventually, corticosteroids were discontinued and he remained on thalidomide (100e200 mg/day). He was noted to have a good response to this combination in August 2002. In January 2004, he presented to his physicians with a chronic painful ulcer in the lower right buccal sulcus. It was noted that the patient had poor oral hygiene and a recent tooth extraction in the area. After a number of unsuccessful conservative debridements, he was referred to our head and neck service. A biopsy confirmed that the boney lesion was osteonecrosis and not a metastatic deposit of myeloma. It was decided that a more extensive debridement would be necessary. He underwent a partial mandibulectomy with an osseocutaneous scapula free flap reconstruction. The skin paddle was used to replace the soft tissue defect caused by the chronic ulcer (Figs. 1e4).
Figure 1 Area of avascular necrosis seen on computerized tomography (CT).
vary from a rapidly progressive disease process to a slow undulating course. Avascular necrosis in patients who have been treated with bisphosphonates is likely due to the inhibition of osteoclastic function, which may be mediated in different ways (Table 1). This will result in reduced bone resorption and therefore the indication for the treatment of
Discussion Bisphosphonates in the form of pamidronate and zoledronate are used regularly in the management of osteoporosis. Although they have been associated with a number of adverse side effects, avascular necrosis of the mandible or maxilla was not reported in phase III trials and until recently, not acknowledged in the product information for these medications. The typical presentation of patients with avascular necrosis is a non-healing extraction socket or a pressure area caused by an ill-fitting denture. Pain, swelling and discharge are followed by the sequestration of bone and the progression may
Figure 2 Area of extensive ulceration adjacent to the necrotic mandible.
96
D.J. Murray et al. Table 1
Mechanism of action of bisphosphonates
Inhibition of monocyte differentiation to osteoclasts3 Increase in osteoclast apoptosis3 Stimulation of osteoclast inhibitory factor1,2,9,10 Prevention of osteoclastic development from bone marrow precursors11 Reduction of osteoclast activity12 Down regulation of matrix metalloproteinases13,14
Figure 3
Harvesting of osseocutaneous scapula free flap.
patients with osteoporosis, bone metastases or multiple myeloma.15 However, bone undergoes osteoclastic bone resorption as part of its normal turnover and inhibiting the resorption of bone in this setting can result in the development of large areas of non-vital bone. As a secondary effect, the lack of cytokines and other bone morphogenic proteins that stimulate the differentiation of osteoblasts will cause a corresponding reduction in the laying down of new mineral. The result is a bone with large areas of non-vital osteoclasts and microfractures of the old bone matrix.12 Another possible mechanism of the action of bisphosphonates has recently been described.13,16
Figure 4 The patient presents at six months postoperatively.
In vitro, zoledronic acid inhibits proliferation of human endothelial cells, basic fibroblast growth factor (bFGF), and vascular endothelial growth factor.13 Santini et al. showed a significant and lasting decrease of VEGF serum levels produced by pamidronate.16 These antiangiogenic properties may also contribute to the relative ischaemia of the affected bone. Although there are a number of bisphosphonates available, there are some differences in their mechanism of action. Those, such as pamidronate and zoledronate, are nitrogen-containing bisphosphonates, and unlike their nitrogen-free counterparts (etidronate and residronate), they accumulate in the bone. It may be this prolonged mechanism that is responsible for the development of avascular bone necrosis that is not seen with the other bisphosphonates. There are many reports of osteonecrosis in patients undergoing chemotherapy 17,18 although the wide range of drugs used in these patients makes it difficult to establish a causal relationship.19 Bisphosphonates have even been advocated for the treatment of avascular necrosis of the femoral head.20 Despite this it is difficult to dismiss the recent rise in the number of cases reported together with the greater understanding of the mechanism of action of the new generation of bisphosphonates. It is possible that the earlier reports of bone necrosis overlooked the influence of these drugs and assumed that the antineoplastic medication or the steroids were solely responsible. It is therefore very probable that bisphosphonates play a significant role in the development of AVN.21 To our knowledge, there have been no reports of avascular necrosis of the long bones associated with the use of bisphosphonates. The mandible and maxilla are unique because of the presence of teeth and periodontal ligaments. Radiotherapy or periodontal infections in the form of periodontitis or periapical disease can be the catalyst for the initiation of the rapid bony destruction that is often reported in these patients.22,7 Tooth extractions can expose the bone to a sudden bacterial colonization. Poorly vascularised bone, with little capacity to repair as a result
Bisphosphonates and avascular necrosis of dampened osteoblastic and osteoclastic activities, would therefore succumb to necrosis and a non-healing socket. Indeed, Marx2,22 and Bagan et al.10 have independently reported 77% and 70%, respectively, of patients with avascular necrosis, who had undergone recent tooth extractions.2,10,22 The manufacturer of zoledronic acid recently included in the drug information leaflet, a recommendation regarding the avoidance of ‘invasive dental procedures’ while on the medication (http://www.pharma.us.novartis.com). Other authors have, however, reported osteonecrosis in patients who had not undergone dental extractions.4 Avascular necrosis is very difficult to treat and debridement is often unsatisfactory8 because areas of previously uninvolved bone become exposed and develop necrosis. Adjunctive treatment such as hyperbaric oxygen has not been shown to be universally effective and discontinuation of the bisphosphonates does not impact significantly on the progression of the disease.1,8,23 Treatments to date have ranged from aggressive debridement of the necrotic and sequestrated bone to more conservative approach, with debridement only in the affected bone. These patients should be treated aggressively with antibiotics to prevent the development of a frank osteomyelitis. Bacteria are a common feature of the sequestra 23,24 and local measures such as irrigation and antimicrobial mouthwash should reduce the number of infective episodes. Sequestration should be allowed to take its natural course and surgical intervention should be considered only when the patient becomes symptomatic. To minimize the risk of developing avascular necrosis of the mandible, prophylaxis and preventive strategies are essential for the patients being treated with bisphosphonates. A screening dental examination prior to the commencement of the medication is imperative. Teeth that require treatment can be identified and those teeth that are not salvageable should be extracted prior to the commencement of bisphosphonates. Patient education regarding gingival health must be stressed. Mouthwashes, particularly those containing chlorhexidine which reduces the overall oral bacterial count,25 should be used regularly by these patients and regular dental examination will reduce the risk of exposing the patient to infections or extractions. Edentulous patients should have a denture assessment to ensure an adequate fit with no areas of mucosal impingement, particularly in the buccal sulci. Extensive manipulation of the dentoalveolar structures (e.g. deep scaling) or occlusal rehabilitative procedures, such as dental implants, should
97 be avoided while these patients are being treated with bisphosphonates. Appropriate indications for the use of these drugs in susceptible patients need to be established. Those who are eucalcaemic (normocalcaemic), or in those with no obvious lytic bony changes should not be prescribed bisphosphonates without other reasons. Bisphosphonates interfere with the osteoblastic/osteoclastic axis and there is an evidence to indicate that this class of drug may be responsible for the increased prevalence of avascular jaw necrosis. This condition causes significant morbidity in a patient population that can ill afford it. Given the obvious beneficial effects of bisphosphonates, and the probable widening of its indications for use as an antitumour medication, it is incumbent on those who prescribe these drugs to be aware of this very serious complication. Prophylactic measures and early diagnosis are essential for the optimal management.
References 1. Ruggiero SL, Mehrotra B, Rosenberg TJ, et al. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004;62(5): 527e34. 2. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003;61(9):1115e7. 3. Wang J, Goodger NM, Pogrel MA. Osteonecrosis of the jaws associated with cancer chemotherapy. J Oral Maxillofac Surg 2003;61(9):1104e7. 4. Maerevoet M, Martin C, Duck L. Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 2005;353(1):99e102 [discussion 99e102]. 5. Durie BG, Katz M, Crowley J. Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 2005;353(1):99e102 [discussion 99e102]. 6. Woo SB, Hande K, Richardson PG. Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 2005;353(1):99e102 [discussion 99e102]. 7. Migliorati CA, Schubert MM, Peterson DE, et al. Bisphosphonate-associated osteonecrosis of mandibular and maxillary bone: an emerging oral complication of supportive cancer therapy. Cancer 2005;104(1):83e93. 8. Zarychanski R, Elphee E, Walton P, et al. Osteonecrosis of the jaw associated with pamidronate therapy. Am J Hematol 2006;81(1):73e5. 9. Vitte C, Fleisch H, Guenther HL. Bisphosphonates induce osteoblasts to secrete an inhibitor of osteoclast-mediated resorption. Endocrinology 1996;137(6):2324e33. 10. Bagan JV, Murillo J, Jimenez Y, et al. Avascular jaw osteonecrosis in association with cancer chemotherapy: series of 10 cases. J Oral Pathol Med 2005;34(2):120e3. 11. Hughes DE, MacDonald BR, Russell RG, et al. Inhibition of osteoclast-like cell formation by bisphosphonates in longterm cultures of human bone marrow. J Clin Invest 1989; 83(6):1930e5.
98 12. Sahni M, Collin P, Felix R, et al. Direct effect of bisphosphonates on isolated rat osteoclasts. J Bone Miner Res 1992; 17(Suppl. 1):189. 13. Wood J, Bonjean K, Ruetz S, et al. Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther 2002;302(3):1055e61. 14. Teronen O, Laitinen M, Salo T, et al. Inhibition of matrix metalloproteinases by bisphosphonates may in part explain their effects in the treatment of multiple myeloma. Blood 2000;96(12):4006e7. 15. Lipton A. Toward new horizons: the future of bisphosphonate therapy. Oncologist 2004;9(Suppl. 4):38e47. 16. Santini D, Vincenzi B, Avvisati G, et al. Pamidronate induces modifications of circulating angiogenetic factors in cancer patients. Clin Cancer Res 2002;8(5):1080e4. 17. Timothy AR, Tucker AK, Malpas JS, et al. Osteonecrosis after intensive chemotherapy for Hodgkin’s disease. Lancet 1978;1(8056):154. 18. Winquist EW, Bauman GS, Balogh J. Nontraumatic osteonecrosis after chemotherapy for testicular cancer: a systematic review. Am J Clin Oncol 2001;24(6):603e6.
D.J. Murray et al. 19. Tarassoff P, Csermak K. Avascular necrosis of the jaws: risk factors in metastatic cancer patients. J Oral Maxillofac Surg 2003;61(10):1238e9. 20. Agarwala S, Sule A, Pai BU, et al. Alendronate in the treatment of avascular necrosis of the hip. Rheumatology (Oxford) 2002;41(3):346e7. 21. Naveau A, Naveau B. Osteonecrosis of the jaw in patients taking bisphosphonates. Joint Bone Spine 2006;73(1):7e9. 22. Marx RE. Osteoradionecrosis: a new concept of its pathophysiology. J Oral Maxillofac Surg 1983;41(5):283e8. 23. Hellstein JW, Marek CL. Bisphosphonate osteochemonecrosis (bis-phossy jaw): is this phossy jaw of the 21st century? J Oral Maxillofac Surg 2005;63(5):682e9. 24. Hellstein JW, Marek CL. Bis-phossy jaw, phossy jaw, and the 21st century: bisphosphonate-associated complications of the jaws. J Oral Maxillofac Surg 2004;62(12):1563e5. 25. Herrera D, Roldan S, Santacruz I, et al. Differences in antimicrobial activity of four commercial 0.12% chlorhexidine mouthrinse formulations: an in vitro contact test and salivary bacterial counts study. J Clin Periodontol 2003;30(4): 307e14.
CASE REPORT
Bisphosphonates and avascular necrosis of the mandible: Case report and review of the literature Dylan J. Murray a,b, Martin J.J. Vesely a,b, Christine B. Novak b, Jonathan Irish b,c, Michael Crump d, Peter C. Neligan a,b,* a
Division of Plastic Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada b Wharton Head & Neck Centre, University Health Network, Toronto, Ontario, Canada c Department of Otolaryngology e Head & Neck Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada d Department of Medical Oncology & Hematology, University Health Network, University of Toronto, Toronto, Ontario, Canada Received 8 May 2006; accepted 6 June 2006
KEYWORDS Bisphosphonates; Avascular necrosis; Cancer; Head and neck; Case report
Summary Background: Avascular necrosis of the mandible or maxilla is being recognized with increasing frequency in patients who are being treated with bisphosphonates for metastatic cancers. Methods and results: A patient who was treated for avascular necrosis following treatment with bisphosphonates for multiple myeloma is presented. Conclusion: Prophylactic and preventative measures should be instituted prior to commencing treatment with bisphosphonates to minimize the risk of developing avascular necrosis. ª 2006 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
Avascular necrosis of the mandible or maxilla has been recognized with increasing frequency in patients who were being treated with bisphosphonates * Corresponding author. Division of Plastic Surgery, Toronto General Hospital, 8N-865 200 Elizabeth Street, Toronto, ON M5G 2C4, Canada. Tel.: þ1 416 340 3449; fax: þ1 416 340 4403. E-mail address: [email protected] (P.C. Neligan).
for metastatic cancers.1e8 A patient who was treated for avascular necrosis following the treatment with bisphosphonates for multiple myeloma is presented. A number of prophylactic and preventative measures should be followed prior to a patient commencing treatment with bisphosphonates to minimize the risk of developing avascular necrosis.
1748-6815/$ - see front matter ª2006BritishAssociationofPlastic,ReconstructiveandAestheticSurgeons.PublishedbyElsevierLtd.Allrightsreserved. doi:10.1016/j.bjps.2006.06.017
Bisphosphonates and avascular necrosis
95
Case report A 60-year-old male presented initially with a lytic scalp lesion and hypocalcaemia. In February 2000, the patient was diagnosed with IgA multiple myeloma. His past social/medical history included alcoholism, hypertension and chronic obstructive airway disease as well as a silent myocardial infarct some years previously. His medical comorbidity precluded stem cell transplantation and he was commenced on standard melphan and prednisone and pamidronate to treat the lytic scalp lesion and the hypocalcaemia. Within a year, he was found to be resistant to the melphan/prednisone combination and was treated with weekly cylophosphamide and alternate day prednisone. This was complicated by severe hyperglycaemia. In April 2002, because of disease progression he began decadron 40 mg daily every 2 weeks combined with thalidomide 200 mg/day. Eventually, corticosteroids were discontinued and he remained on thalidomide (100e200 mg/day). He was noted to have a good response to this combination in August 2002. In January 2004, he presented to his physicians with a chronic painful ulcer in the lower right buccal sulcus. It was noted that the patient had poor oral hygiene and a recent tooth extraction in the area. After a number of unsuccessful conservative debridements, he was referred to our head and neck service. A biopsy confirmed that the boney lesion was osteonecrosis and not a metastatic deposit of myeloma. It was decided that a more extensive debridement would be necessary. He underwent a partial mandibulectomy with an osseocutaneous scapula free flap reconstruction. The skin paddle was used to replace the soft tissue defect caused by the chronic ulcer (Figs. 1e4).
Figure 1 Area of avascular necrosis seen on computerized tomography (CT).
vary from a rapidly progressive disease process to a slow undulating course. Avascular necrosis in patients who have been treated with bisphosphonates is likely due to the inhibition of osteoclastic function, which may be mediated in different ways (Table 1). This will result in reduced bone resorption and therefore the indication for the treatment of
Discussion Bisphosphonates in the form of pamidronate and zoledronate are used regularly in the management of osteoporosis. Although they have been associated with a number of adverse side effects, avascular necrosis of the mandible or maxilla was not reported in phase III trials and until recently, not acknowledged in the product information for these medications. The typical presentation of patients with avascular necrosis is a non-healing extraction socket or a pressure area caused by an ill-fitting denture. Pain, swelling and discharge are followed by the sequestration of bone and the progression may
Figure 2 Area of extensive ulceration adjacent to the necrotic mandible.
96
D.J. Murray et al. Table 1
Mechanism of action of bisphosphonates
Inhibition of monocyte differentiation to osteoclasts3 Increase in osteoclast apoptosis3 Stimulation of osteoclast inhibitory factor1,2,9,10 Prevention of osteoclastic development from bone marrow precursors11 Reduction of osteoclast activity12 Down regulation of matrix metalloproteinases13,14
Figure 3
Harvesting of osseocutaneous scapula free flap.
patients with osteoporosis, bone metastases or multiple myeloma.15 However, bone undergoes osteoclastic bone resorption as part of its normal turnover and inhibiting the resorption of bone in this setting can result in the development of large areas of non-vital bone. As a secondary effect, the lack of cytokines and other bone morphogenic proteins that stimulate the differentiation of osteoblasts will cause a corresponding reduction in the laying down of new mineral. The result is a bone with large areas of non-vital osteoclasts and microfractures of the old bone matrix.12 Another possible mechanism of the action of bisphosphonates has recently been described.13,16
Figure 4 The patient presents at six months postoperatively.
In vitro, zoledronic acid inhibits proliferation of human endothelial cells, basic fibroblast growth factor (bFGF), and vascular endothelial growth factor.13 Santini et al. showed a significant and lasting decrease of VEGF serum levels produced by pamidronate.16 These antiangiogenic properties may also contribute to the relative ischaemia of the affected bone. Although there are a number of bisphosphonates available, there are some differences in their mechanism of action. Those, such as pamidronate and zoledronate, are nitrogen-containing bisphosphonates, and unlike their nitrogen-free counterparts (etidronate and residronate), they accumulate in the bone. It may be this prolonged mechanism that is responsible for the development of avascular bone necrosis that is not seen with the other bisphosphonates. There are many reports of osteonecrosis in patients undergoing chemotherapy 17,18 although the wide range of drugs used in these patients makes it difficult to establish a causal relationship.19 Bisphosphonates have even been advocated for the treatment of avascular necrosis of the femoral head.20 Despite this it is difficult to dismiss the recent rise in the number of cases reported together with the greater understanding of the mechanism of action of the new generation of bisphosphonates. It is possible that the earlier reports of bone necrosis overlooked the influence of these drugs and assumed that the antineoplastic medication or the steroids were solely responsible. It is therefore very probable that bisphosphonates play a significant role in the development of AVN.21 To our knowledge, there have been no reports of avascular necrosis of the long bones associated with the use of bisphosphonates. The mandible and maxilla are unique because of the presence of teeth and periodontal ligaments. Radiotherapy or periodontal infections in the form of periodontitis or periapical disease can be the catalyst for the initiation of the rapid bony destruction that is often reported in these patients.22,7 Tooth extractions can expose the bone to a sudden bacterial colonization. Poorly vascularised bone, with little capacity to repair as a result
Bisphosphonates and avascular necrosis of dampened osteoblastic and osteoclastic activities, would therefore succumb to necrosis and a non-healing socket. Indeed, Marx2,22 and Bagan et al.10 have independently reported 77% and 70%, respectively, of patients with avascular necrosis, who had undergone recent tooth extractions.2,10,22 The manufacturer of zoledronic acid recently included in the drug information leaflet, a recommendation regarding the avoidance of ‘invasive dental procedures’ while on the medication (http://www.pharma.us.novartis.com). Other authors have, however, reported osteonecrosis in patients who had not undergone dental extractions.4 Avascular necrosis is very difficult to treat and debridement is often unsatisfactory8 because areas of previously uninvolved bone become exposed and develop necrosis. Adjunctive treatment such as hyperbaric oxygen has not been shown to be universally effective and discontinuation of the bisphosphonates does not impact significantly on the progression of the disease.1,8,23 Treatments to date have ranged from aggressive debridement of the necrotic and sequestrated bone to more conservative approach, with debridement only in the affected bone. These patients should be treated aggressively with antibiotics to prevent the development of a frank osteomyelitis. Bacteria are a common feature of the sequestra 23,24 and local measures such as irrigation and antimicrobial mouthwash should reduce the number of infective episodes. Sequestration should be allowed to take its natural course and surgical intervention should be considered only when the patient becomes symptomatic. To minimize the risk of developing avascular necrosis of the mandible, prophylaxis and preventive strategies are essential for the patients being treated with bisphosphonates. A screening dental examination prior to the commencement of the medication is imperative. Teeth that require treatment can be identified and those teeth that are not salvageable should be extracted prior to the commencement of bisphosphonates. Patient education regarding gingival health must be stressed. Mouthwashes, particularly those containing chlorhexidine which reduces the overall oral bacterial count,25 should be used regularly by these patients and regular dental examination will reduce the risk of exposing the patient to infections or extractions. Edentulous patients should have a denture assessment to ensure an adequate fit with no areas of mucosal impingement, particularly in the buccal sulci. Extensive manipulation of the dentoalveolar structures (e.g. deep scaling) or occlusal rehabilitative procedures, such as dental implants, should
97 be avoided while these patients are being treated with bisphosphonates. Appropriate indications for the use of these drugs in susceptible patients need to be established. Those who are eucalcaemic (normocalcaemic), or in those with no obvious lytic bony changes should not be prescribed bisphosphonates without other reasons. Bisphosphonates interfere with the osteoblastic/osteoclastic axis and there is an evidence to indicate that this class of drug may be responsible for the increased prevalence of avascular jaw necrosis. This condition causes significant morbidity in a patient population that can ill afford it. Given the obvious beneficial effects of bisphosphonates, and the probable widening of its indications for use as an antitumour medication, it is incumbent on those who prescribe these drugs to be aware of this very serious complication. Prophylactic measures and early diagnosis are essential for the optimal management.
References 1. Ruggiero SL, Mehrotra B, Rosenberg TJ, et al. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004;62(5): 527e34. 2. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003;61(9):1115e7. 3. Wang J, Goodger NM, Pogrel MA. Osteonecrosis of the jaws associated with cancer chemotherapy. J Oral Maxillofac Surg 2003;61(9):1104e7. 4. Maerevoet M, Martin C, Duck L. Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 2005;353(1):99e102 [discussion 99e102]. 5. Durie BG, Katz M, Crowley J. Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 2005;353(1):99e102 [discussion 99e102]. 6. Woo SB, Hande K, Richardson PG. Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 2005;353(1):99e102 [discussion 99e102]. 7. Migliorati CA, Schubert MM, Peterson DE, et al. Bisphosphonate-associated osteonecrosis of mandibular and maxillary bone: an emerging oral complication of supportive cancer therapy. Cancer 2005;104(1):83e93. 8. Zarychanski R, Elphee E, Walton P, et al. Osteonecrosis of the jaw associated with pamidronate therapy. Am J Hematol 2006;81(1):73e5. 9. Vitte C, Fleisch H, Guenther HL. Bisphosphonates induce osteoblasts to secrete an inhibitor of osteoclast-mediated resorption. Endocrinology 1996;137(6):2324e33. 10. Bagan JV, Murillo J, Jimenez Y, et al. Avascular jaw osteonecrosis in association with cancer chemotherapy: series of 10 cases. J Oral Pathol Med 2005;34(2):120e3. 11. Hughes DE, MacDonald BR, Russell RG, et al. Inhibition of osteoclast-like cell formation by bisphosphonates in longterm cultures of human bone marrow. J Clin Invest 1989; 83(6):1930e5.
98 12. Sahni M, Collin P, Felix R, et al. Direct effect of bisphosphonates on isolated rat osteoclasts. J Bone Miner Res 1992; 17(Suppl. 1):189. 13. Wood J, Bonjean K, Ruetz S, et al. Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther 2002;302(3):1055e61. 14. Teronen O, Laitinen M, Salo T, et al. Inhibition of matrix metalloproteinases by bisphosphonates may in part explain their effects in the treatment of multiple myeloma. Blood 2000;96(12):4006e7. 15. Lipton A. Toward new horizons: the future of bisphosphonate therapy. Oncologist 2004;9(Suppl. 4):38e47. 16. Santini D, Vincenzi B, Avvisati G, et al. Pamidronate induces modifications of circulating angiogenetic factors in cancer patients. Clin Cancer Res 2002;8(5):1080e4. 17. Timothy AR, Tucker AK, Malpas JS, et al. Osteonecrosis after intensive chemotherapy for Hodgkin’s disease. Lancet 1978;1(8056):154. 18. Winquist EW, Bauman GS, Balogh J. Nontraumatic osteonecrosis after chemotherapy for testicular cancer: a systematic review. Am J Clin Oncol 2001;24(6):603e6.
D.J. Murray et al. 19. Tarassoff P, Csermak K. Avascular necrosis of the jaws: risk factors in metastatic cancer patients. J Oral Maxillofac Surg 2003;61(10):1238e9. 20. Agarwala S, Sule A, Pai BU, et al. Alendronate in the treatment of avascular necrosis of the hip. Rheumatology (Oxford) 2002;41(3):346e7. 21. Naveau A, Naveau B. Osteonecrosis of the jaw in patients taking bisphosphonates. Joint Bone Spine 2006;73(1):7e9. 22. Marx RE. Osteoradionecrosis: a new concept of its pathophysiology. J Oral Maxillofac Surg 1983;41(5):283e8. 23. Hellstein JW, Marek CL. Bisphosphonate osteochemonecrosis (bis-phossy jaw): is this phossy jaw of the 21st century? J Oral Maxillofac Surg 2005;63(5):682e9. 24. Hellstein JW, Marek CL. Bis-phossy jaw, phossy jaw, and the 21st century: bisphosphonate-associated complications of the jaws. J Oral Maxillofac Surg 2004;62(12):1563e5. 25. Herrera D, Roldan S, Santacruz I, et al. Differences in antimicrobial activity of four commercial 0.12% chlorhexidine mouthrinse formulations: an in vitro contact test and salivary bacterial counts study. J Clin Periodontol 2003;30(4): 307e14.