- Email: [email protected]
Oral osteonecrosis associated with the use of ibandronate: report of a case and clinical implications
Oral osteonecrosis associated with the use of ibandronate: report of a case and clinical implications Cesar A. Migliorati, DDS, MS, PhD,a Basil N. Armonis, MD,b and Ourania Nicolatou-Galitis, DDS,c Fort Lauderdale, FL, and Athens, Greece NSU COLLEGE OF DENTAL MEDICINE, 6TH IKA ONCOLOGY HOSPITAL, AND UNIVERSITY OF ATHENS
A breast cancer patient with skeletal metastases was treated with only one IV dose of ibandronate in March of 2005 and subsequent doses of oral ibandronate 50 mg daily. One year after the IV infusion, the patient complained of oral pain under her lower denture. After several negative attempts from her dentist to control the pain and adjust the denture, the patient was diagnosed with bisphosphonate-associated osteonecrosis (BON) of the mandible. The use of ibandronate, a potent bisphosphonate, is increasing worldwide. Prescribing oncologists should be aware of the potential for the developement of new cases of BON in a similar fashion as with zoledronic acid. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;106:e18-e21)
This report discusses a case of a patient treated with only one intravenous (IV) dose of ibandronate (Hoffman-La Roche, Basel, Switzerland) in March of 2005 and subsequent doses of oral ibandronate 50 mg daily, who a year later was diagnosed with bisphosphonateassociated osteonecrosis (BON). Bisphosphonates have been used in oncology as part of standard of care in the treatment of hypercalcemia of malignancy and the prevention of skeletal-related events in patients with tumors metastatic to bone.1-3 Ibandronate is a newer and potent nitrogen-containing form of bisphosphonate in use in over 40 countries worldwide, except the United States, for the prevention of skeletal events (pathological fractures, bone complications requiring radiotherapy or surgery) in patients with breast cancer and bone metastases and in the treatment of tumor-induced hypercalcemia with or without metastases.4,5 The drug is available in both IV and oral formulations.6,7 Cancer patients are usually treated with an IV infusion of 6 mg. It is recommended that the infusion should be done in not less than 15 minutes to prevent renal toxicity. The oral formulation is given daily (50-mg tablets). In addition to the treatment of cancer patients, oral and intravenous formulations of the drug are used worldwide for the treatment a
Oral Medicine Specialist, Professor of Oral Medicine, NSU College of Dental Medicine, Fort Lauderdale, FL. b Medical Oncologist, 6th IKA Oncology Hospital, Department of Medical Oncology, Athens, Greece. c Oral Medicine Specialist, Dental Oncology Unit, Clinic of Hospital Dentistry, School of Dentistry, University of Athens, Athens, Greece. Received for publication Oct 24, 2007; returned for revision Feb 25, 2008; accepted for publication Mar 5, 2008. 1079-2104/$ - see front matter © 2008 Mosby, Inc. All rights reserved. doi:10.1016/j.tripleo.2008.03.005
e18
of patients with postmenopausal osteoporosis. The use of both formulations of ibandronate was recently approved in the United States for the treatment of postmenopausal osteoporosis.8 BON is a recently reported oral complication associated with the use of bisphosphonates and considered a long-term oral complication of supportive cancer therapy.9 Cases of untreatable osteonecrosis of the mandible and maxilla have been reported not only in patients with cancer metastatic to bone, but also, albeit in a smaller number, in osteoporosis patients taking a bisphosphonate.10-12 Most of the cases of BON reported so far affect patients taking the IV formulations (pamidronate and zoledronic acid)10; however, a smaller number of cases of BON in patients taking the oral bisphosphonates have also been diagnosed.13 Bisphosphonates are potent inhibitors of osteoclastic bone resorption.14-16 The medication has a strong inhibitory effect on osteoclasts and induces apoptosis.14 This oral complication affects elderly cancer patients, and those with multiple myeloma appear to be at higher risk.17 Although the etiology of BON is unknown, it is believed to be associated with the potent suppression of bone remodeling induced by the bisphosphonates.9,12; however, this remains to be proven. Risk factors for BON development have been discussed in the literature, including dental extraction and oral trauma, the type of bisphosphonate and the antiresorption potency, the drug exposure time, and the absorption and bioavailability of the drug being used by the patient.18 The basic disease (malignancy or osteoporosis/osteopenia) also seems to play a role.18 CASE REPORT A 78-year-old female was seen at the Dental Oncology Clinic of the University of Athens in Greece for the evalua-
OOOOE Volume 106, Number 1
Fig. 1. Note clinically visible exposed necrotic bone in 2 areas of the mandibular alveolar ridge (arrows).
tion of oral complaints on July 25, 2007. In 2003, the patient had full-mandibular extraction with normal postoperatory healing. In July of 2006, the patient visited her dentist complaining of oral pain. At the time of the consultation, the patient was wearing a partial maxillary denture and a mandibular full denture. The oral pain and discomfort were being caused by the mandibular denture, which was replaced at that time. In addition to the new mandibular denture and several denture adjustment procedures, the dentist prescribed antibiotics to help alleviate the pain. The patient remained under reasonable pain control until July of 2007, when the pain increased and the dentist referred her for further evaluation by an oral medicine specialist at the University of Athens. At the time of this consultation, the medical history revealed that in May of 1989 the patient had been diagnosed with grade III ductal adenocarcinoma of the right breast. She was initially treated with a modified radical mastectomy of the right breast with lymph node dissection of the ipsilateral axilla. Neoplastic infiltration was found in 2 of 13 of the axillary nodes removed. The patient received adjuvant antihormonal therapy with tamoxifen 20 mg daily that continued for the following 5 years. In August of 2004, the patient presented to the medical oncologist with multiple sites of metastatic disease of the spine (L2-5 and T10). In September of 2004 she was treated with radiation therapy of the spine for a total dose of 40 Gy. She was also treated with oral letrozole (Femara) 2.5 mg daily for nearly 2 years. For some time during the chemotherapy she also received methylprednisolone (Medrol) 16 mg daily. In March of 2005, because of the skeletal involvement, the patient was given 1 initial IV infusion of ibandronate sodium (Bondronat), 6 mg in 15 minutes, followed by daily oral administration of 50-mg capsules until the time of the oral medicine consultation in July of 2007. The breast cancer progressed to produce further metastatic lesions in the
Migliorati et al. e19 liver and the right supraclavicular fossa. At this time, in November of 2006, the patient was treated with megestrol acetate (Megace) 160 mg daily to replace letrozole. Because of further disease progression in March of 2007, the patient discontinued the antihormonal therapy and started chemotherapy with oral vinorelbine (Navelbine) 60 mg/m2 weekly. This treatment produced mixed response leading to stabilization of the disease in some sites and disease progression in others. Because of disease progression in the liver in June of 2007, the patient discontinued vinorelbine and started IV liposomal doxorubicin (Myocet) 60 mg/m2 every 3 weeks. The new therapy resulted in considerable clinical improvement of her oncological disease. In addition to breast cancer, the patient presented other medical comorbidities including Parkinson’s disease diagnosed in 1996 and treated with levodopa, benserazide HCL (Madopar), and entacapone (Comtan). At the time of the oral medicine consultation, the patient presented with obvious areas of osteonecrosis on the mandible in 2 different sites. One of the areas was inflamed and purulent secretion was easily visible (Fig. 1, arrows). The panoramic radiograph revealed an ill-defined radiolucency on the anterior mandible (Fig. 2). At this point, considering the patient’s medical history and the treatment of the skeletal complications with a potent bisphosphonate, the clinical and radiographic presentation, and the lack of response to the clinical attempts to resolve the problem, the diagnosis of bisphosphonate-associated osteonecrosis (BON) was confirmed. In addition, it was confirmed that the patient did not have a past history of radiation therapy to the head and neck. At this time, the patient was explained about the nature of BON and the probable association with ibandronate. She was started on the clinical protocol for the management of BON of the Dental Oncology Unit, University of Athens. The protocol consisted of clindamycin (Dalacin) 500 mg every 8 hours, miconazole (Daktarin) oral gel, and chlorhexidine mouthwashes 3 times daily. The pain subsided but clindamycin had to be replaced by azithromycin (Zithromax) because of gastric adverse events. The patient’s symptoms improved and she is currently under close followup. The dentures are adjusted as needed. Further clinical intervention will be decided depending on the progress of the osteonecrotic process and the progress of the cancer. Because of her metastatic disease and because of the reasonable oral control of the osteonecrotic process, the patient continues to take oral ibandronate sodium 50 mg daily.
DISCUSSION The present case, although not the first of its nature reported in the literature, illustrates the clear potential for ibandronate to cause BON. In this case, dental extraction cannot be considered a trigger. We believe that denture trauma may have initiated the process of osteonecrosis when the patient first complained of pain in June of 2006. Recently, a single case of BON was reported to the dental literature19 in a breast cancer patient who apparently developed BON only 1 month into the therapy with IV ibandronate infusion. The report does not state whether or not other bisphospho-
e20
Migliorati et al.
OOOOE July 2008
Fig. 2. Note areas of radiolucency at the crest of the alveolar ridge that correspond to the areas of clinically exposed necrotic bone (arrows).
nate drugs had also been used before this adverse event. Assuming that ibandronate was the only bisphosphonate therapy given to the patient, the development of BON after only 1 IV infusion and a few daily doses of oral ibandronate (50 mg) is highly significant. Previous case reports and literature reviews also mentioned the existence of other additional cases of BON associated with ibandronate use but details of the cases were not available.13 Oral ibandronate was only recently approved for use in the United States for the treatment of osteoporosis. However, in a recent work presented at ASCO 2007, the RADAR group20 reported 6 cases of BON associated with the use of oral ibandronate that had been reported to the Food and Drug Administration (FDA) until 2005. Ibandronate is a potent nitrogen-containing bisphosphonate that could have the relative bone resorption capacity similar to that of zoledronic acid.14 Its use in Europe and other parts of the world has increased in recent years. Current studies have suggested that important safety profiles might favor the use of ibandronate over zoledronic acid and pamidronate. It has been demonstrated that IV infusion of ibandronate reduces the incidence of skeletal complications in patients with breast cancer and metastatic bone disease.5 Renal safety was demonstrated to be comparable to placebo and could be maintained in extended therapy.21 The
evaluation of renal safety in a subset group of elderly individuals (ⱖ 65 years) suggested that ibandronate might be renal safe even in the elderly patient.22 The safety profile of ibandronate is further demonstrated in patients with multiple myeloma with and without impaired renal function and in patients with metastatic bone disease and osteoporosis.22,23 In addition, unique to all other types of bisphosphonates, oral ibandronate has a similar gastrointestinal toxicity profile when compared to placebo.24 A cost-effectiveness study with oral ibandronate, IV zoledronic acid, and IV pamidronate evaluated the treatment of bone metastases in patients on hormonal therapy for breast cancer in the United Kingdom. The study demonstrated that oral ibandronate was cost effective for the management of bone metastases from breast cancer patients by providing effective management of skeletal-related events and bone pain management while avoiding resource use and cost associated with IV infusions.25 In this case report, the patient was treated with many different medications including letrozole, megestrol, vinorelbine, doxorubicin, and methylprednisolone in addition to the ibandronate. There is no evidence in the literature that these medications could also cause oral osteonecrosis. This has been recently confirmed in a prospective study of 80 patients with multiple myeloma and other malignancies.26 The increase in the number of BON case reports
OOOOE Volume 106, Number 1
associated with oral and IV ibandronate concomitant to the increase in the use of this medication should be an alert to medical oncologists and to all physicians who prescribe this medication. There is strong evidence of the possibility for this potent nitrogen-containing bisphosphonate to cause this serious complication in the jawbones. Preventive oral care for stabilization of oral health before the start of therapy is recommended, independent of the type of bisphosphonate that the patient is going to use. It is possible that genetic polymorphisms could increase the risk for the complication. However, at the present time we cannot predict what factors increase the risk for BON in a small group of patients taking bisphosphonates. Therefore, both the prescribing physician and the dentist should carefully monitor all patients throughout bisphosphonate therapy.
Migliorati et al. e21
13.
14. 15.
16.
17.
18.
REFERENCES 1. Hillner BE, Ingle JN, Chlebowski RT, Gralow J, Yee G, Janjan N, et al. American Society of Clinical Oncology 2003 Update on the Role of Bisphosphonates and Bone Health Issues in Women With Breast Cancer. J Clin Oncol 2003;21:4042-57. 2. Body JJ. Bisphosphonates for malignancy-related bone disease: current status, future developments. Support Care Cancer 2006;14:408-18. 3. Bobba RS, Beattie K, Parkinson B B, Kumbhare D, Adachi JD. Tolerability of different dosing regimens of bisphosphonates for the treatment of osteoporosis and malignant disease. Drug Saf 2006;29:1133-52. 4. Tripathy D, Body JJ, Diel I, Bergstrom B. Alleviation of bone pain with oral and intravenous ibandronate in women with metastatic breast cancer. Eur J Cancer 2003;1(Suppl.5):S136. 5. Body JJ, Diel IJ, Bergstrom B, Kreuser ED, Dornoff W, Gorbunova VA, et al. Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases. Ann Oncol 2003;14:1399-405. 6. Bondronat intravenous formulation, product information for Europe. Available at: http://www.bondronat.com/gear/contents/ servlet/staticfilesServlet?type⫽data&communityId⫽re714004& id⫽static/attachedfile/re7300002/re71700003/AttachedFile_ 03549.pdf. Accessed September 24, 2007. 7. Bondronat oral formulation, product information for Europe. Available at: http://www.bondronat.com/gear/contents/servlet/ staticfilesServlet?type⫽data&communityId⫽re714004&id⫽ static/attachedfile/re7300002/re71700003/AttachedFile_ 03551.pdf. Accessed September 24, 2007. 8. Boniva oral/intravenous formulations, prescribing information. Available at: http://www.rocheusa.com/products/Boniva/PI.pdf. Accessed September 24, 2007. 9. Migliorati CA, Siegel MA, Elting LS. Bisphosphonate-associated osteonecrosis: a long-term complication of bisphosphonate treatment. Lancet Oncol 2006;7:508-14. 10. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003;61:1115-7. 11. 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. 12. Migliorati CA, Schubert MM, Peterson DE, Seneda LM. Bisphosphonate-associated osteonecrosis of mandibular and
19. 20.
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24.
25.
26.
maxillary bone: an emerging oral complication of supportive care in cancer. Cancer 2005;104:83-93. Woo S-B, Hellstein JW, Kalmar JR. Systematic review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 2006;144:753-61. Licata AA. Discovery, clinical development, and therapeutic uses of bisphosphonates. Ann Pharmacother 2005;39:668-77. Mashiba T, Mori S, Burr DB, Komatsubara S, Cao Y, Manabe T, et al. The effects of suppressed bone remodeling by bisphosphonates on microdamage accumulation and degree of mineralization in the cortical bone of dog rib. J Bone Miner Metab 2005;23(suppl):36-42. Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CYC. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 2005;90:1294-1301. Marx RE, Sawatari Y, Fortin M, Broumand V. Bisphosphonateinduced exposed bone (osteonecrosis.osteopetrosis) of the jaws: risk factors, recognition, prevention and treatment. J Oral Maxillofac Surg 2005;63:1567-75. Migliorati CA, Casiglia J, Epstein J, Jacobsen PL, Siegel MA, Woo SB. Managing the care of patients with bisphosphonateassociated osteonecrosis. An American Academy of Oral Medicine position paper. J Am Dent Assoc 2005;136:1658-68. Malden NJ, Pai AY. Oral bisphosphonate associated osteonecrosis of the jaws: three case reports. Br Dent J 2007;203:93-7. Edwards BJ, Gounder M, McKoy JM, Raisch D, Farrugia M, Migliorati C, et al. Bisphosphonate use and osteonecrosis of the jaw: pharmacovigilance and reporting of this serious adverse event from the Research on Adverse Drug Events and Reports (RADAR) project. J Clin Oncol 2007;25(18s):June Supplement, Abstract 6519. Body JJ, Coleman R, Clezardin P, Ripamonti C, Rizzoli Y, Aapro M. International society of geriatric oncology (SIOG) clinical practice recommendations for the use of bisphosphonates in the elderly. Eur J Cancer 2007;43:852-8. Strampel W, Emkey R, Civitelli R. Safety considerations with bisphosphonates for the treatment of osteoporosis. Drug Saf 2007;30:755-63. Bergner R, Henrich DM, Hoffmann M, Honecker A, Mikus G, Nauth B, et al. Renal safety and pharmacokinectics of ibandronate in multiple myeloma patients with or without impaired renal function. J Clin Pharmacol 2007;47:942-50. Bobba RS, Beattie K, Parkinson B, Kumbhare D, Adachi JD. Tolerability of different dosing of bisphosphonates for the treatment of osteoporosis and malignant bone disease. Drug Saf 2006;29:1133-52. De Cock E, Hutton J, Canney P, Body JJ, Barret-Lee P, Neary MP, et al. Cost-effectiveness of oral ibandronate versus IV zoledronic acid or IV pamidronate for bone metastases in patients receiving oral hormonal therapy for breast cancer in the United Kingdom. Clin Ther 2005;27:1295-1310. Boonyapakorn T, Schirmer I, Reichart PA, Sturm I, Massenkeil G. Bisphosphonate-induced osteonecrosis of the jaws: prospective study of 80 patients with multiple myeloma and other malignancies. Oral Oncol 2008 [epub ahead of press].
Reprint requests: Cesar A. Migliorati, DDS, MS, PhD Department of Diagnostic Sciences NSU College of Dental Medicine 3200 S. University Dr. Fort Lauderdale, FL 33328 [email protected]
A breast cancer patient with skeletal metastases was treated with only one IV dose of ibandronate in March of 2005 and subsequent doses of oral ibandronate 50 mg daily. One year after the IV infusion, the patient complained of oral pain under her lower denture. After several negative attempts from her dentist to control the pain and adjust the denture, the patient was diagnosed with bisphosphonate-associated osteonecrosis (BON) of the mandible. The use of ibandronate, a potent bisphosphonate, is increasing worldwide. Prescribing oncologists should be aware of the potential for the developement of new cases of BON in a similar fashion as with zoledronic acid. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;106:e18-e21)
This report discusses a case of a patient treated with only one intravenous (IV) dose of ibandronate (Hoffman-La Roche, Basel, Switzerland) in March of 2005 and subsequent doses of oral ibandronate 50 mg daily, who a year later was diagnosed with bisphosphonateassociated osteonecrosis (BON). Bisphosphonates have been used in oncology as part of standard of care in the treatment of hypercalcemia of malignancy and the prevention of skeletal-related events in patients with tumors metastatic to bone.1-3 Ibandronate is a newer and potent nitrogen-containing form of bisphosphonate in use in over 40 countries worldwide, except the United States, for the prevention of skeletal events (pathological fractures, bone complications requiring radiotherapy or surgery) in patients with breast cancer and bone metastases and in the treatment of tumor-induced hypercalcemia with or without metastases.4,5 The drug is available in both IV and oral formulations.6,7 Cancer patients are usually treated with an IV infusion of 6 mg. It is recommended that the infusion should be done in not less than 15 minutes to prevent renal toxicity. The oral formulation is given daily (50-mg tablets). In addition to the treatment of cancer patients, oral and intravenous formulations of the drug are used worldwide for the treatment a
Oral Medicine Specialist, Professor of Oral Medicine, NSU College of Dental Medicine, Fort Lauderdale, FL. b Medical Oncologist, 6th IKA Oncology Hospital, Department of Medical Oncology, Athens, Greece. c Oral Medicine Specialist, Dental Oncology Unit, Clinic of Hospital Dentistry, School of Dentistry, University of Athens, Athens, Greece. Received for publication Oct 24, 2007; returned for revision Feb 25, 2008; accepted for publication Mar 5, 2008. 1079-2104/$ - see front matter © 2008 Mosby, Inc. All rights reserved. doi:10.1016/j.tripleo.2008.03.005
e18
of patients with postmenopausal osteoporosis. The use of both formulations of ibandronate was recently approved in the United States for the treatment of postmenopausal osteoporosis.8 BON is a recently reported oral complication associated with the use of bisphosphonates and considered a long-term oral complication of supportive cancer therapy.9 Cases of untreatable osteonecrosis of the mandible and maxilla have been reported not only in patients with cancer metastatic to bone, but also, albeit in a smaller number, in osteoporosis patients taking a bisphosphonate.10-12 Most of the cases of BON reported so far affect patients taking the IV formulations (pamidronate and zoledronic acid)10; however, a smaller number of cases of BON in patients taking the oral bisphosphonates have also been diagnosed.13 Bisphosphonates are potent inhibitors of osteoclastic bone resorption.14-16 The medication has a strong inhibitory effect on osteoclasts and induces apoptosis.14 This oral complication affects elderly cancer patients, and those with multiple myeloma appear to be at higher risk.17 Although the etiology of BON is unknown, it is believed to be associated with the potent suppression of bone remodeling induced by the bisphosphonates.9,12; however, this remains to be proven. Risk factors for BON development have been discussed in the literature, including dental extraction and oral trauma, the type of bisphosphonate and the antiresorption potency, the drug exposure time, and the absorption and bioavailability of the drug being used by the patient.18 The basic disease (malignancy or osteoporosis/osteopenia) also seems to play a role.18 CASE REPORT A 78-year-old female was seen at the Dental Oncology Clinic of the University of Athens in Greece for the evalua-
OOOOE Volume 106, Number 1
Fig. 1. Note clinically visible exposed necrotic bone in 2 areas of the mandibular alveolar ridge (arrows).
tion of oral complaints on July 25, 2007. In 2003, the patient had full-mandibular extraction with normal postoperatory healing. In July of 2006, the patient visited her dentist complaining of oral pain. At the time of the consultation, the patient was wearing a partial maxillary denture and a mandibular full denture. The oral pain and discomfort were being caused by the mandibular denture, which was replaced at that time. In addition to the new mandibular denture and several denture adjustment procedures, the dentist prescribed antibiotics to help alleviate the pain. The patient remained under reasonable pain control until July of 2007, when the pain increased and the dentist referred her for further evaluation by an oral medicine specialist at the University of Athens. At the time of this consultation, the medical history revealed that in May of 1989 the patient had been diagnosed with grade III ductal adenocarcinoma of the right breast. She was initially treated with a modified radical mastectomy of the right breast with lymph node dissection of the ipsilateral axilla. Neoplastic infiltration was found in 2 of 13 of the axillary nodes removed. The patient received adjuvant antihormonal therapy with tamoxifen 20 mg daily that continued for the following 5 years. In August of 2004, the patient presented to the medical oncologist with multiple sites of metastatic disease of the spine (L2-5 and T10). In September of 2004 she was treated with radiation therapy of the spine for a total dose of 40 Gy. She was also treated with oral letrozole (Femara) 2.5 mg daily for nearly 2 years. For some time during the chemotherapy she also received methylprednisolone (Medrol) 16 mg daily. In March of 2005, because of the skeletal involvement, the patient was given 1 initial IV infusion of ibandronate sodium (Bondronat), 6 mg in 15 minutes, followed by daily oral administration of 50-mg capsules until the time of the oral medicine consultation in July of 2007. The breast cancer progressed to produce further metastatic lesions in the
Migliorati et al. e19 liver and the right supraclavicular fossa. At this time, in November of 2006, the patient was treated with megestrol acetate (Megace) 160 mg daily to replace letrozole. Because of further disease progression in March of 2007, the patient discontinued the antihormonal therapy and started chemotherapy with oral vinorelbine (Navelbine) 60 mg/m2 weekly. This treatment produced mixed response leading to stabilization of the disease in some sites and disease progression in others. Because of disease progression in the liver in June of 2007, the patient discontinued vinorelbine and started IV liposomal doxorubicin (Myocet) 60 mg/m2 every 3 weeks. The new therapy resulted in considerable clinical improvement of her oncological disease. In addition to breast cancer, the patient presented other medical comorbidities including Parkinson’s disease diagnosed in 1996 and treated with levodopa, benserazide HCL (Madopar), and entacapone (Comtan). At the time of the oral medicine consultation, the patient presented with obvious areas of osteonecrosis on the mandible in 2 different sites. One of the areas was inflamed and purulent secretion was easily visible (Fig. 1, arrows). The panoramic radiograph revealed an ill-defined radiolucency on the anterior mandible (Fig. 2). At this point, considering the patient’s medical history and the treatment of the skeletal complications with a potent bisphosphonate, the clinical and radiographic presentation, and the lack of response to the clinical attempts to resolve the problem, the diagnosis of bisphosphonate-associated osteonecrosis (BON) was confirmed. In addition, it was confirmed that the patient did not have a past history of radiation therapy to the head and neck. At this time, the patient was explained about the nature of BON and the probable association with ibandronate. She was started on the clinical protocol for the management of BON of the Dental Oncology Unit, University of Athens. The protocol consisted of clindamycin (Dalacin) 500 mg every 8 hours, miconazole (Daktarin) oral gel, and chlorhexidine mouthwashes 3 times daily. The pain subsided but clindamycin had to be replaced by azithromycin (Zithromax) because of gastric adverse events. The patient’s symptoms improved and she is currently under close followup. The dentures are adjusted as needed. Further clinical intervention will be decided depending on the progress of the osteonecrotic process and the progress of the cancer. Because of her metastatic disease and because of the reasonable oral control of the osteonecrotic process, the patient continues to take oral ibandronate sodium 50 mg daily.
DISCUSSION The present case, although not the first of its nature reported in the literature, illustrates the clear potential for ibandronate to cause BON. In this case, dental extraction cannot be considered a trigger. We believe that denture trauma may have initiated the process of osteonecrosis when the patient first complained of pain in June of 2006. Recently, a single case of BON was reported to the dental literature19 in a breast cancer patient who apparently developed BON only 1 month into the therapy with IV ibandronate infusion. The report does not state whether or not other bisphospho-
e20
Migliorati et al.
OOOOE July 2008
Fig. 2. Note areas of radiolucency at the crest of the alveolar ridge that correspond to the areas of clinically exposed necrotic bone (arrows).
nate drugs had also been used before this adverse event. Assuming that ibandronate was the only bisphosphonate therapy given to the patient, the development of BON after only 1 IV infusion and a few daily doses of oral ibandronate (50 mg) is highly significant. Previous case reports and literature reviews also mentioned the existence of other additional cases of BON associated with ibandronate use but details of the cases were not available.13 Oral ibandronate was only recently approved for use in the United States for the treatment of osteoporosis. However, in a recent work presented at ASCO 2007, the RADAR group20 reported 6 cases of BON associated with the use of oral ibandronate that had been reported to the Food and Drug Administration (FDA) until 2005. Ibandronate is a potent nitrogen-containing bisphosphonate that could have the relative bone resorption capacity similar to that of zoledronic acid.14 Its use in Europe and other parts of the world has increased in recent years. Current studies have suggested that important safety profiles might favor the use of ibandronate over zoledronic acid and pamidronate. It has been demonstrated that IV infusion of ibandronate reduces the incidence of skeletal complications in patients with breast cancer and metastatic bone disease.5 Renal safety was demonstrated to be comparable to placebo and could be maintained in extended therapy.21 The
evaluation of renal safety in a subset group of elderly individuals (ⱖ 65 years) suggested that ibandronate might be renal safe even in the elderly patient.22 The safety profile of ibandronate is further demonstrated in patients with multiple myeloma with and without impaired renal function and in patients with metastatic bone disease and osteoporosis.22,23 In addition, unique to all other types of bisphosphonates, oral ibandronate has a similar gastrointestinal toxicity profile when compared to placebo.24 A cost-effectiveness study with oral ibandronate, IV zoledronic acid, and IV pamidronate evaluated the treatment of bone metastases in patients on hormonal therapy for breast cancer in the United Kingdom. The study demonstrated that oral ibandronate was cost effective for the management of bone metastases from breast cancer patients by providing effective management of skeletal-related events and bone pain management while avoiding resource use and cost associated with IV infusions.25 In this case report, the patient was treated with many different medications including letrozole, megestrol, vinorelbine, doxorubicin, and methylprednisolone in addition to the ibandronate. There is no evidence in the literature that these medications could also cause oral osteonecrosis. This has been recently confirmed in a prospective study of 80 patients with multiple myeloma and other malignancies.26 The increase in the number of BON case reports
OOOOE Volume 106, Number 1
associated with oral and IV ibandronate concomitant to the increase in the use of this medication should be an alert to medical oncologists and to all physicians who prescribe this medication. There is strong evidence of the possibility for this potent nitrogen-containing bisphosphonate to cause this serious complication in the jawbones. Preventive oral care for stabilization of oral health before the start of therapy is recommended, independent of the type of bisphosphonate that the patient is going to use. It is possible that genetic polymorphisms could increase the risk for the complication. However, at the present time we cannot predict what factors increase the risk for BON in a small group of patients taking bisphosphonates. Therefore, both the prescribing physician and the dentist should carefully monitor all patients throughout bisphosphonate therapy.
Migliorati et al. e21
13.
14. 15.
16.
17.
18.
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Reprint requests: Cesar A. Migliorati, DDS, MS, PhD Department of Diagnostic Sciences NSU College of Dental Medicine 3200 S. University Dr. Fort Lauderdale, FL 33328 [email protected]