Osteonecrosis of the Jaw in Cancer After Treatment With Bisphosphonates: Incidence and Risk Factors
http://www.100md.com
《临床肿瘤学》
the Department of Clinical Therapeutics, Department of Hygiene and Epidemiology, and Department of Radiology, Medical School, University of Athens
H. Dunant Hospital
Department of Hematology, 251 General Air Force Hospital, Athens, Greece
ABSTRACT
PURPOSE: Osteonecrosis of the jaw (ONJ) has been associated recently with the use of pamidronate and zoledronic acid. We studied the incidence, characteristics, and risk factors for the development of ONJ among patients treated with bisphosphonates for bone metastases.
PATIENTS AND METHODS: ONJ was assessed prospectively since July 2003. The first bisphosphonate treatment among patients with ONJ was administered in 1997. Two hundred fifty-two patients who received bisphosphonates since January 1997 were included in this analysis.
RESULTS: Seventeen patients (6.7%) developed ONJ: 11 of 111 (9.9%) with multiple myeloma, two of 70 (2.9%) with breast cancer, three of 46 (6.5%) with prostate cancer, and one of 25 (4%) with other neoplasms (P = .289). The median number of treatment cycles and time of exposure to bisphosphonates were 35 infusions and 39.3 months for patients with ONJ compared with 15 infusions (P < .001) and 19 months (P = .001), respectively, for patients with no ONJ. The incidence of ONJ increased with time to exposure from 1.5% among patients treated for 4 to 12 months to 7.7% for treatment of 37 to 48 months. The cumulative hazard was significantly higher with zoledronic acid compared with pamidronate alone or pamidronate and zoledronic acid sequentially (P < .001). All but two patients with ONJ had a history of dental procedures within the last year or use of dentures.
CONCLUSION: The use of bisphosphonates seems to be associated with the development of ONJ. Length of exposure seems to be the most important risk factor for this complication. The type of bisphosphonate may play a role and previous dental procedures may be a precipitating factor.
INTRODUCTION
Bisphosphonates are synthetic analogs of the naturally occurring pyrophosphate. They accumulate to sites of active bone formation, making the sites more resistant to dissolution by osteoclasts, and are internalized by osteoclasts reducing their survival and modulating the signaling from osteoblasts to osteoclasts.1 During the last decade, more potent bisphosphonates have been used.2
Bisphosphonates have been approved for the treatment of cancer-related hypercalcemia and bone involvement by multiple myeloma (MM) and solid tumors.3-7 Adverse effects associated with the use of bisphosphonates are infrequent and consist of pyrexia, renal function impairment, and hypocalcemia. Recently, a new complication associated with their use has been described: avascular osteonecrosis of the jaw (ONJ).8-15 ONJ was initially associated with the use of zoledronic acid but occurrences after pamidronate use have also been reported.8,9 Several issues need to be clarified: the pathophysiologic mechanism underlying ONJ, and the incidence, possible risk factors, prevention, and appropriate treatment. Bisphosphonate-associated ONJ has been described in various malignancies and it has been suggested that its development requires a long period of exposure.9,10 The diagnosis of osteonecrosis, in most cases, was made retrospectively, based on the review of medical records rather than by a specialist. Furthermore, a denominator for the patients who were diagnosed with ONJ was not established.
After the first reports of ONJ appeared in the literature, every patient in our center who was treated with bisphosphonates and had dental problems was assessed by a maxillofacial surgeon who confirmed the diagnosis and treated the patient. To define the incidence of ONJ as well as its association with specific risk factors, we analyzed the medical records of all patients with cancer who received bisphosphonates in our department during an 8-year period.
PATIENTS AND METHODS
Our first patient with bisphosphonate-associated ONJ was diagnosed in July 2003. Since then, 16 additional patients receiving bisphosphonates were prospectively diagnosed with ONJ. The diagnosis of ONJ was suspected by the presence of symptoms and signs, such as pain, soft-tissue swelling, or exposed bone, especially after dental work. All patients with suspected ONJ were referred to a maxillofacial surgeon (I.M.) for additional evaluation and treatment. All patients had panoramic x-rays to rule out other etiologies, whereas biopsy was performed only when exclusion of metastatic disease was necessary. The earliest initiation of bisphosphonate treatment among these patients was in 1997. Therefore, we studied patients who were treated with bisphosphonate from January 1, 1997. The medical records of all patients who were included in the analysis were reviewed to exclude symptoms and signs of ONJ: no patient with a high probability of ONJ was identified.
To ensure adequate exposure to the drugs, we included patients who started treatment with a bisphosphonate until December 31, 2003 and received at least six infusions. Patients were observed until February 2005. Pamidronate at 90 mg was administered as a 2-hour infusion every 4 to 5 weeks, zoledronic acid was administered at 4 mg every 4 to 6 weeks during 15 minutes, and ibandronate was administered at 4 mg during 2 hours every 4 to 6 weeks. Patients who developed osteonecrosis were no longer treated with bisphosphonates.
Statistical Analysis
Time of exposure to bisphosphonates was defined as the time in months from the initial infusion of bisphosphonates to the last recorded infusion. All analyses were performed using the SPSS statistical software (SPSS for Windows, version 12.1; SPSS Inc, Chicago, IL). The 2 test was used for comparisons of proportions across levels of categoric variables. For continuous variables, the t test or the Mann-Whitney U test was used for the comparison of the means or the medians, respectively. Survival analysis was used to estimate the hazard of developing osteonecrosis; time of exposure to bisphosphonates was the primary time variable. In this analysis, subjects who did not develop osteonecrosis while receiving treatment were censored, whereas the focal event was diagnosis of osteonecrosis. Hazard functions of developing ONJ according to the use of thalidomide (yes or no), primary site (myeloma, breast, or prostate), and type of bisphosphonate used (zoledronic acid v pamidronate ± zoledronic acid) were compared using the log-rank test. Throughout the analysis, a level of 5% was used to denote statistical significance.
RESULTS
Patients
The baseline characteristics of the 252 patients included in our analysis are listed in Table 1. Other diagnoses included carcinoma of the lung (n = 7), cervix (n = 3), bladder (n = 4), endometrium (n = 3), unknown origin (n = 2), stomach (n = 1), kidney (n = 1), ovaries (n = 1), colon (n = 1), lymphoma (n = 1), and Langerhans cell histiocytosis (n = 1). One hundred five patients were treated with zoledronic acid, 58 patients were treated with pamidronate, and five patients were treated with ibandronate, whereas 69 patients received pamidronate and zoledronic acid sequentially and 15 patients received zoledronic acid and ibandronate sequentially. Patients with MM routinely received pulse dexamethasone 40 mg for 4 days every 4 weeks as part of their treatment, whereas patients with solid tumors received corticosteroids only in association with taxane-based chemotherapy (on days –1, 0, and occasionally days 1 through 3 after treatment every 2 to 3 weeks).
Exposure to Bisphosphonates and Development of Osteonecrosis
The median number of bisphosphonate infusions administered to the whole population was 15 (range, six to 74) and median time of exposure was 20 months (range, four to 86 months). MM patients received a median of 23 infusions (range, six to 74 infusions), breast cancer patients received a median of 14.5 cycles (range, six to 56 cycles), prostate cancer patients received a median of 12 cycles (range, six to 56 cycles), and patients with other neoplasms received a median of 10 cycles (range, six to 21 cycles).
Seventeen patients (6.7%) were diagnosed with osteonecrosis of the jaw: 11 (9.9%) of 111 patients with MM, two (2.9%) of 70 with breast cancer, three (6.5%) of 46 with prostate cancer, and one (4%) of 25 with other neoplasms. There was no association of the development of osteonecrosis with primary site (P = .289), sex (P = .258), or age (P = .247). All occurrences of ONJ were diagnosed in patients who were treated with zoledronic acid either alone (seven patients; 6.7%) or after pamidronate (nine patients; 13%), or preceding ibandronic acid (one patient; 6.7%). The association of osteonecrosis with the type of bisphosphonate showed a marginal statistical significance (P = .063; Table 1). Among patients with MM, six (8.8%) of 68 patients who received thalidomide and five (12.2%) of 43 patients who did not were diagnosed with osteonecrosis (P = .571).
Time of exposure to bisphosphonates was strongly associated with the development of ONJ (Table 2). No patient who received fewer than 13 treatments with bisphosphonates developed osteonecrosis. Patients who developed ONJ received a median number of 35 infusions (range, 13 to 68 infusions), whereas the respective number for patients with no osteonecrosis was 15 infusions (range, six to 74 infusions; P < .0001). Median time of exposure to bisphosphonates was 39.3 months for patients with osteonecrosis (range, 11 to 86 months), compared with 19 months (four to 84.7 months) for patients with no osteonecrosis (P = .001).
Figure 1 shows the cumulative hazard of developing ONJ for the whole population. Table 3 shows the cumulative hazard at various time points after the initiation of treatment with bisphosphonates. The cumulative hazard increased above 1% after 12 months of treatment up to 11% at 4 years. In analyses of hazards according to treatment with thalidomide, no significant difference was evident in the respective rates (P = .362). There was also no significant difference according to the primary site (myeloma, breast, prostate, other; P = .06). For type of bisphosphonates administered (according to the grouping in Table 1), a significant difference in the respective hazards of developing ONJ was seen (P = .003). To further study this difference, we compared the cumulative hazard rates between patients who received zoledronic acid alone versus those who received pamidronate alone or with subsequent zoledronic acid. The hazard of developing ONJ was significantly higher in the zoledronic acid group (P < .001; Fig 2A). The hazard was 1% within the first year of treatment, increasing to 21% at 3 years for zoledronic acid, whereas the hazard among the other group was 0% for the first 2 years, increasing to only 7% after 4 years of treatment (Table 3).
Given that time of exposure was different among patients with different primary sites or different type of bisphosphonates administered (Table 1), we also compared the hazards of developing ONJ between different levels of the indicated factors at 48 months post-treatment initiation. This time point was chosen according to the maximum time of exposure of the subgroup with the smallest range. Patients who received treatment beyond these points were censored, independently of whether they subsequently developed ONJ. There was no significant difference in the hazards between different primary sites (P = .517). On the contrary, the hazard was significantly higher in the zoledronic acid group compared with pamidronate alone or with subsequent zoledronic acid (P = .005; Fig 2B).
Characteristics and Management of Patients With ONJ
The characteristics of the 17 patients with osteonecrosis are summarized in Table 4. No patient had received radiation at the area of the head and neck. At the time of diagnosis of ONJ, three patients (17.6%) were receiving chemotherapy, two patients (12%) were receiving an aromatase inhibitor, and 10 patients (59%) were receiving corticosteroids, whereas two patients (12%) had received corticosteroids in the past. The remaining five patients (29%) had never received corticosteroids.
Fourteen patients had osteonecrosis of the mandible and three patients had osteonecrosis of the maxilla. In all patients pain was the presenting symptom, whereas patients who had prior dental extraction or artificial dentures had also purulent discharge. In two patients who had not had previous dental extraction or dentures, destabilization of their teeth occurred. In 13 patients dental extraction within the last year preceded the diagnosis of osteonecrosis, two patients had dentures, and two patients had no prior procedures in the oral cavity. Diagnosis was clinical in 11 patients, whereas biopsy was obtained in six patients to exclude metastatic disease. Necrotic bone was the only histologic finding, with surrounding bacteria but no evidence of bacterial invasion in the area of necrosis. Bisphosphonate infusions were discontinued after the confirmation of diagnosis. Management of all patients was conservative. Only minor debridement procedures were attempted to reduce sharp edges and trauma to surrounding tissues. All patients received multiple courses of antibiotics. The initial regimen contained amoxicillin or amoxicillin/clavulanate or metronidazole. Improvement of oral hygiene was recommended and oral rinses of chlorhexidine were prescribed. Measures were taken to reduce the contact of artificial dentures with the exposed bone.
Treatment with antibiotics resulted in transient improvement, but only one patient showed sustained improvement of osteonecrosis after multiple courses of antibiotics. The other 16 patients had persistent disability, mainly consisting of recurrences with purulent discharge and pain after the discontinuation of the antibiotics. One patient received hyperbaric oxygen without improvement. The minimum follow-up after the development of osteonecrosis has been 4 months (range, 4 to 24 months) and the lack of symptomatic or radiologic improvement in these 16 patients indicates that bone defects are permanent.
DISCUSSION
Osteonecrosis refers to the death of the bone as a result of impaired blood supply to the affected areas. Cancer and its treatment have been described as risk factors for the development of osteonecrosis.16 The most common site of osteonecrosis is the femoral head. Avascular ONJ has been associated predominantly with radiation of the head and neck, known as osteoradionecrosis,17 but has also been described after chemotherapy.18,19 Recently, ONJ has been reported after treatment with the bisphosphonates pamidronate and zoledronic acid in cancer patients.8-15 Although these reports make the association of bisphosphonate and the development of ONJ likely, the true incidence of osteonecrosis is unknown. The first attempt to determine true incidence was reported by Durie et al,10 who performed a Web-based survey in 1,203 patients with MM and breast cancer receiving bisphosphonates. Some limitations of the study include the fact that the diagnosis of ONJ was based on the answers given by the patients and that patients with dental problems might have been more responsive to the survey. We attempted to overcome this problem by prospectively studying the development of osteonecrosis during the last 2 years. This is the first analysis using this methodology; we believe this method overcomes some of the limitations of the previous reports and provides a denominator for the development of ONJ. Furthermore, our analysis is the first to include all types of cancer patients and thus provides the opportunity to assess possible differences among different primary sites. A limitation, common for all reports up to now, is its retrospective nature. Retrospective studies are subject to biases, the most important of which may have been introduced by the increased awareness of this adverse effect after 2003. We attempted to minimize that effect by selecting patients based on the time of exposure of patients with documented ONJ. We cannot exclude the possibility that a few patients before that time point may have been missed. Nevertheless, this number is likely to be small, given that ONJ causes intense symptoms, which cannot remain unrecognized.
The incidence of osteonecrosis in MM patients was 9.9% and the incidence in breast cancer patients was 2.9%, which are slightly different from those of Durie et al10 for documented osteonecrosis (6.8% and 4.4%, respectively). The difference in the incidence between myeloma and breast cancer in our series is not significant and is most probably due to the different time of exposure between these groups. Indeed, our analysis indicated that the time of exposure to the drug and the number of infusions are the most significant risk factors for development of osteonecrosis. None of our patients who received fewer than 12 bisphosphonate infusions has developed ONJ, whereas the median exposure to the drug for patients who developed ONJ was almost twice that of patients who did not. Similar observations have been reported in abstract form by Durie et al.20 Our analysis suggested a continuous increase in the incidence even after 5 years of exposure. Nevertheless, these results should be viewed with caution because of the small number of patients who have had such long exposure.
The type of bisphosphonate may play a role in the development of ONJ. This complication has been described exclusively after exposure to nitrogen-containing bisphosphonates pamidronate and zoledronic acid. Furthermore, Durie et al10 suggested that the risk is higher with zoledronic acid than with pamidronate. The difference between the two types of bisphosphonates is even sharper in our study. We did not observe any occurrences of ONJ with pamidronate alone, although there were nine occurrences among 69 patients (13%) treated with pamidronate and zoledronic acid sequentially. The difference in the hazard between zoledronic acid and pamidronate plus or minus zoledronic acid was significant, indicating that the development of ONJ occurs earlier with treatment with zoledronic acid. The reason for this difference is unknown. A possible explanation is the more potent inhibitory effect of zoledronic acid on bone turnover compared with pamidronate. Pamidronate is approximately 100- to 700-fold more potent than etidronate, whereas ibandronate and zoledronic acid show 10,000- to 100,000-fold greater potency than etidronate.21 Furthermore, zoledronic acid produced a greater reduction of collagen type-I degradation products (N-telopeptide) than pamidronate in a recent study,22 confirming the stronger antiresorptive activity of zoledronic acid. Thus, we may assume that the continuous, potent decrease in bone turnover caused by zoledronic acid may lead to increased bone fragility in the long run and, in combination with other local factors that are present in the jaw, to the development of ONJ.
Impaired blood supply has been implicated in the development of ONJ.23 There have been several reports indicating that zoledronic acid has antiangiogenic activity.24-26 This might explain its association with ONJ and the difference compared with pamidronate, the antiangiogenic properties of which are less established. We also studied the effect of thalidomide, an effective antimyeloma agent27 with antiangiogenic properties. We found no association of thalidomide use with the development of ONJ.
None of our patients who received ibandronate alone developed osteonecrosis. Ibandronate has only been approved recently for bone metastases from breast cancer and, thus, a longer follow-up is required until its association with ONJ can be accurately assessed.
Apart from time of exposure and type of bisphosphonates, corticosteroids and chemotherapy have been implicated in the development of ONJ.16,18,19,28 Most patients who developed osteonecrosis had been treated with one or both. Nevertheless, one patient with renal cancer had never received either corticosteroids or chemotherapy, whereas five patients had never received corticosteroids. Because of the diversity of the chemotherapy regimens and the timing of administration, it was impossible to perform an analysis addressing the contribution of this factor in the development of ONJ. Similarly, there was considerable diversity regarding the use of corticosteroids among the patients included in our study. The contribution of corticosteroids in the development of bisphosphonates-induced ONJ should be addressed in properly designed studies. It has been speculated that dental procedures may be the precipitating factor,8,10,11 as indeed was the case for most of our patients. Nevertheless, no dental procedures or use of dentures were reported in two patients.
We conclude that ONJ is a complication that is correlated with long-term use of bisphosphonates; this complication has received much publicity and developed much controversy recently.29,30 This might have implications in the current standards of use of these drugs in cancer patients. The American Society of Clinical Oncology guidelines for MM31 and breast cancer32 suggest that bisphosphonates should be administered "until there is evidence of a substantial decline in the patient's general performance status." Taking into consideration the natural history of these diseases, this could result in administration of bisphosphonates to some patients for several years. Nevertheless, the studies on which current guidelines were based usually administered bisphosphonates for a maximum of 2 years.7,33-35 In view of the data reported by us as well as by others,10,15,19 caution is required for use of pamidronate and zoledronic acid beyond 2 years. Furthermore, patients should improve their oral hygiene, whereas oncologists and dentists should be aware of this complication and its management. This is also emphasized by new postmarketing guidelines issued for pamidronate and zoledronic acid.36 Reinitiating bisphosphonate therapy in patients suffering from osteonecrosis is debated and warrants additional study. Prospective randomized studies are needed to assess the incidence of ONJ and the safety of bisphosphonates in cancer patients.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
NOTES
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Russell RG, Rogers MJ: Bisphosphonates: From the laboratory to the clinic and back again. Bone 25: 97-106, 1999
Stewart AF: Clinical practice: Hypercalcemia associated with cancer. N Engl J Med 352: 373-379, 2005
Hillner BE, Ingle JN, Berenson JR, et al: American Society of Clinical Oncology guidelines on the role of bisphosphonates in breast cancer. J Clin Oncol 18: 1378-1391, 2000
Saad F: Treatment of bone complications in advanced prostate cancer: Rationale for bisphosphonate use and results of a phase III trial with zoledronic acid. Semin Oncol 29: S19-S27, 2002 (suppl 21)
Rosen LS: Efficacy and safety of zoledronic acid in the treatment of bone metastases associated with lung cancer and other solid tumors. Semin Oncol 29: S28-S32, 2002 (suppl 21)
Rosen LS, Gordon D, Tchekmedyian S, et al: Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: A phase III, double-blind, randomized trial—the Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol 21: 3150-3157, 2003
Marx RE: Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: A growing epidemic. J Oral Maxillofac Surg 61: 1115-1117, 2003
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 62: 527-534, 2004
Durie BGM, Katz M, Crowley J: Osteonecrosis of the jaws and bisphosphonates. N Engl J Med 353: 99, 2005
Bagan JV, Murillo J, Jimenez Y, et al: Avascular jaw osteonecrosis in association with cancer chemotherapy: Series of 10 cases. J Oral Pathol Med 34: 120-123, 2005
Melo MD, Obeid G: Osteonecrosis of the maxilla in a patient with a history of bisphosphonate therapy. J Can Dent Assoc 71: 111-113, 2005
Vannucchi AM, Ficarra G, Antonioli E, et al: Osteonecrosis of the jaw associated with zoledronate therapy in a patient with multiple myeloma. Br J Haematol 128: 738, 2005
Migliorati CA: Bisphosphonates and oral cavity avascular bone necrosis. J Clin Oncol 21: 4253-4254, 2003
Singhal S, Kut V, Tariman J, et al: Pamidronate and zoledronate-associated osteonecrosis in myeloma is an increasing and under-recognized problem. Haematologica 90: 191, 2005 (abstr)
Assouline-Dayan Y, Chang C, Greenspan A, et al: Pathogenesis and natural history of osteonecrosis. Semin Arthritis Rheum 32: 94-124, 2002
Oh HK, Chambers MS, Garden AS, et al: Risk of osteoradionecrosis after extraction of impacted third molars in irradiated head and neck cancer patients. J Oral Maxillofac Surg 62: 139-144, 2004
Schwartz HC: Osteonecrosis of the jaws: A complication of cancer chemotherapy. Head Neck Surg 4: 251-253, 1982
Sung EC, Chan SM, Sakurai K, et al: Osteonecrosis of the maxilla as a complication to chemotherapy: A case report. Spec Care Dentist 22: 142-146, 2002
Durie BGM, Katz M, McCoy J, et al: Osteonecrosis of the jaws in myeloma: Analysis of risk factors including time dependency of Aredia and Zometa use, steroid use and underlying dental problems. Haematologica 90: 190, 2005 (abstr)
Lin JH: Bisphosphonates: A review of their pharmacokinetic properties. Bone 18: 75-85, 1996
Rosen LS, Gordon D, Kaminski M, et al: Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: A phase III, double-blind, comparative trial. Cancer J 7: 377-387, 2001
Shankland WE: Medullary and odontogenic disease in the painful jaw: Clinicopathological review of 500 cases. Cranio 20: 295-303, 2002
Wood J, Bonjean K, Ruetz S, et al: Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther 302: 1055-1061, 2002
Vincenzi B, Santini D, Dicuonzo G, et al: Zoledronic acid-related angiogenesis modifications and survival in advanced breast cancer patients. J Interferon Cytokine Res 25: 144-151, 2005
Santini D, Vincenzi B, Dicuonzo G, et al: Zoledronic acid induces significant and long-lasting modifications of circulating angiogenic factors in cancer patients. Clin Cancer Res 9: 2893-2897, 2003
Bamias A, Dimopoulos MA: Thalidomide and immunomodulatory drugs in the treatment of cancer. Expert Opin Investig Drugs 14: 45-55, 2005
Mattano LA Jr, Sather HN, Trigg ME, et al: Osteonecrosis as a complication of treating acute lymphoblastic leukemia in children: A report from the Children's cancer group. J Clin Oncol 18: 3262-3272, 2000
Robinson NA: Biphosphonates: A word of caution. Ann Acad Med Singapore 33: S48-S49, 2004 (suppl)
Tarasoff P, Csermak K: Avascular necrosis of the jaws: Risk factors in metastatic cancer patients. J Oral Maxillofac Surg 61: 1238-1239, 2003
Berenson JR, Hillner BE, Kyle RA, et al: American Society of Clinical Oncology Clinical Practice guidelines: The role of bisphosphonates in multiple myeloma. J Clin Oncol 20: 3719-3736, 2002
Hillner BE, Ingle JN, Chlebowski RT, 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 21: 4042-4057, 2003
Berenson JR, Lichtenstein A, Porter L, et al: Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. N Engl J Med 334: 488-493, 1996
Hortobayi GN, Theriault RL, Lipton A, et al: Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. J Clin Oncol 16: 2038-2044, 1998
Lipton A, Theriault RL, Hortobayi GN, et al: Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: Long-term follow up of two randomized, placebo-controlled trials. Cancer 88: 1082-1090, 2000
Package Insert Revisions re: Osteonecrosis of the jaw: Zometa (zoledronic acid) injection and Aredia (pamidronate disodium) injection. Oncologic Drugs Advisory Committee Meeting, March 4, 2005. http://www.fda.gov(Aristotle Bamias, Efstath)
H. Dunant Hospital
Department of Hematology, 251 General Air Force Hospital, Athens, Greece
ABSTRACT
PURPOSE: Osteonecrosis of the jaw (ONJ) has been associated recently with the use of pamidronate and zoledronic acid. We studied the incidence, characteristics, and risk factors for the development of ONJ among patients treated with bisphosphonates for bone metastases.
PATIENTS AND METHODS: ONJ was assessed prospectively since July 2003. The first bisphosphonate treatment among patients with ONJ was administered in 1997. Two hundred fifty-two patients who received bisphosphonates since January 1997 were included in this analysis.
RESULTS: Seventeen patients (6.7%) developed ONJ: 11 of 111 (9.9%) with multiple myeloma, two of 70 (2.9%) with breast cancer, three of 46 (6.5%) with prostate cancer, and one of 25 (4%) with other neoplasms (P = .289). The median number of treatment cycles and time of exposure to bisphosphonates were 35 infusions and 39.3 months for patients with ONJ compared with 15 infusions (P < .001) and 19 months (P = .001), respectively, for patients with no ONJ. The incidence of ONJ increased with time to exposure from 1.5% among patients treated for 4 to 12 months to 7.7% for treatment of 37 to 48 months. The cumulative hazard was significantly higher with zoledronic acid compared with pamidronate alone or pamidronate and zoledronic acid sequentially (P < .001). All but two patients with ONJ had a history of dental procedures within the last year or use of dentures.
CONCLUSION: The use of bisphosphonates seems to be associated with the development of ONJ. Length of exposure seems to be the most important risk factor for this complication. The type of bisphosphonate may play a role and previous dental procedures may be a precipitating factor.
INTRODUCTION
Bisphosphonates are synthetic analogs of the naturally occurring pyrophosphate. They accumulate to sites of active bone formation, making the sites more resistant to dissolution by osteoclasts, and are internalized by osteoclasts reducing their survival and modulating the signaling from osteoblasts to osteoclasts.1 During the last decade, more potent bisphosphonates have been used.2
Bisphosphonates have been approved for the treatment of cancer-related hypercalcemia and bone involvement by multiple myeloma (MM) and solid tumors.3-7 Adverse effects associated with the use of bisphosphonates are infrequent and consist of pyrexia, renal function impairment, and hypocalcemia. Recently, a new complication associated with their use has been described: avascular osteonecrosis of the jaw (ONJ).8-15 ONJ was initially associated with the use of zoledronic acid but occurrences after pamidronate use have also been reported.8,9 Several issues need to be clarified: the pathophysiologic mechanism underlying ONJ, and the incidence, possible risk factors, prevention, and appropriate treatment. Bisphosphonate-associated ONJ has been described in various malignancies and it has been suggested that its development requires a long period of exposure.9,10 The diagnosis of osteonecrosis, in most cases, was made retrospectively, based on the review of medical records rather than by a specialist. Furthermore, a denominator for the patients who were diagnosed with ONJ was not established.
After the first reports of ONJ appeared in the literature, every patient in our center who was treated with bisphosphonates and had dental problems was assessed by a maxillofacial surgeon who confirmed the diagnosis and treated the patient. To define the incidence of ONJ as well as its association with specific risk factors, we analyzed the medical records of all patients with cancer who received bisphosphonates in our department during an 8-year period.
PATIENTS AND METHODS
Our first patient with bisphosphonate-associated ONJ was diagnosed in July 2003. Since then, 16 additional patients receiving bisphosphonates were prospectively diagnosed with ONJ. The diagnosis of ONJ was suspected by the presence of symptoms and signs, such as pain, soft-tissue swelling, or exposed bone, especially after dental work. All patients with suspected ONJ were referred to a maxillofacial surgeon (I.M.) for additional evaluation and treatment. All patients had panoramic x-rays to rule out other etiologies, whereas biopsy was performed only when exclusion of metastatic disease was necessary. The earliest initiation of bisphosphonate treatment among these patients was in 1997. Therefore, we studied patients who were treated with bisphosphonate from January 1, 1997. The medical records of all patients who were included in the analysis were reviewed to exclude symptoms and signs of ONJ: no patient with a high probability of ONJ was identified.
To ensure adequate exposure to the drugs, we included patients who started treatment with a bisphosphonate until December 31, 2003 and received at least six infusions. Patients were observed until February 2005. Pamidronate at 90 mg was administered as a 2-hour infusion every 4 to 5 weeks, zoledronic acid was administered at 4 mg every 4 to 6 weeks during 15 minutes, and ibandronate was administered at 4 mg during 2 hours every 4 to 6 weeks. Patients who developed osteonecrosis were no longer treated with bisphosphonates.
Statistical Analysis
Time of exposure to bisphosphonates was defined as the time in months from the initial infusion of bisphosphonates to the last recorded infusion. All analyses were performed using the SPSS statistical software (SPSS for Windows, version 12.1; SPSS Inc, Chicago, IL). The 2 test was used for comparisons of proportions across levels of categoric variables. For continuous variables, the t test or the Mann-Whitney U test was used for the comparison of the means or the medians, respectively. Survival analysis was used to estimate the hazard of developing osteonecrosis; time of exposure to bisphosphonates was the primary time variable. In this analysis, subjects who did not develop osteonecrosis while receiving treatment were censored, whereas the focal event was diagnosis of osteonecrosis. Hazard functions of developing ONJ according to the use of thalidomide (yes or no), primary site (myeloma, breast, or prostate), and type of bisphosphonate used (zoledronic acid v pamidronate ± zoledronic acid) were compared using the log-rank test. Throughout the analysis, a level of 5% was used to denote statistical significance.
RESULTS
Patients
The baseline characteristics of the 252 patients included in our analysis are listed in Table 1. Other diagnoses included carcinoma of the lung (n = 7), cervix (n = 3), bladder (n = 4), endometrium (n = 3), unknown origin (n = 2), stomach (n = 1), kidney (n = 1), ovaries (n = 1), colon (n = 1), lymphoma (n = 1), and Langerhans cell histiocytosis (n = 1). One hundred five patients were treated with zoledronic acid, 58 patients were treated with pamidronate, and five patients were treated with ibandronate, whereas 69 patients received pamidronate and zoledronic acid sequentially and 15 patients received zoledronic acid and ibandronate sequentially. Patients with MM routinely received pulse dexamethasone 40 mg for 4 days every 4 weeks as part of their treatment, whereas patients with solid tumors received corticosteroids only in association with taxane-based chemotherapy (on days –1, 0, and occasionally days 1 through 3 after treatment every 2 to 3 weeks).
Exposure to Bisphosphonates and Development of Osteonecrosis
The median number of bisphosphonate infusions administered to the whole population was 15 (range, six to 74) and median time of exposure was 20 months (range, four to 86 months). MM patients received a median of 23 infusions (range, six to 74 infusions), breast cancer patients received a median of 14.5 cycles (range, six to 56 cycles), prostate cancer patients received a median of 12 cycles (range, six to 56 cycles), and patients with other neoplasms received a median of 10 cycles (range, six to 21 cycles).
Seventeen patients (6.7%) were diagnosed with osteonecrosis of the jaw: 11 (9.9%) of 111 patients with MM, two (2.9%) of 70 with breast cancer, three (6.5%) of 46 with prostate cancer, and one (4%) of 25 with other neoplasms. There was no association of the development of osteonecrosis with primary site (P = .289), sex (P = .258), or age (P = .247). All occurrences of ONJ were diagnosed in patients who were treated with zoledronic acid either alone (seven patients; 6.7%) or after pamidronate (nine patients; 13%), or preceding ibandronic acid (one patient; 6.7%). The association of osteonecrosis with the type of bisphosphonate showed a marginal statistical significance (P = .063; Table 1). Among patients with MM, six (8.8%) of 68 patients who received thalidomide and five (12.2%) of 43 patients who did not were diagnosed with osteonecrosis (P = .571).
Time of exposure to bisphosphonates was strongly associated with the development of ONJ (Table 2). No patient who received fewer than 13 treatments with bisphosphonates developed osteonecrosis. Patients who developed ONJ received a median number of 35 infusions (range, 13 to 68 infusions), whereas the respective number for patients with no osteonecrosis was 15 infusions (range, six to 74 infusions; P < .0001). Median time of exposure to bisphosphonates was 39.3 months for patients with osteonecrosis (range, 11 to 86 months), compared with 19 months (four to 84.7 months) for patients with no osteonecrosis (P = .001).
Figure 1 shows the cumulative hazard of developing ONJ for the whole population. Table 3 shows the cumulative hazard at various time points after the initiation of treatment with bisphosphonates. The cumulative hazard increased above 1% after 12 months of treatment up to 11% at 4 years. In analyses of hazards according to treatment with thalidomide, no significant difference was evident in the respective rates (P = .362). There was also no significant difference according to the primary site (myeloma, breast, prostate, other; P = .06). For type of bisphosphonates administered (according to the grouping in Table 1), a significant difference in the respective hazards of developing ONJ was seen (P = .003). To further study this difference, we compared the cumulative hazard rates between patients who received zoledronic acid alone versus those who received pamidronate alone or with subsequent zoledronic acid. The hazard of developing ONJ was significantly higher in the zoledronic acid group (P < .001; Fig 2A). The hazard was 1% within the first year of treatment, increasing to 21% at 3 years for zoledronic acid, whereas the hazard among the other group was 0% for the first 2 years, increasing to only 7% after 4 years of treatment (Table 3).
Given that time of exposure was different among patients with different primary sites or different type of bisphosphonates administered (Table 1), we also compared the hazards of developing ONJ between different levels of the indicated factors at 48 months post-treatment initiation. This time point was chosen according to the maximum time of exposure of the subgroup with the smallest range. Patients who received treatment beyond these points were censored, independently of whether they subsequently developed ONJ. There was no significant difference in the hazards between different primary sites (P = .517). On the contrary, the hazard was significantly higher in the zoledronic acid group compared with pamidronate alone or with subsequent zoledronic acid (P = .005; Fig 2B).
Characteristics and Management of Patients With ONJ
The characteristics of the 17 patients with osteonecrosis are summarized in Table 4. No patient had received radiation at the area of the head and neck. At the time of diagnosis of ONJ, three patients (17.6%) were receiving chemotherapy, two patients (12%) were receiving an aromatase inhibitor, and 10 patients (59%) were receiving corticosteroids, whereas two patients (12%) had received corticosteroids in the past. The remaining five patients (29%) had never received corticosteroids.
Fourteen patients had osteonecrosis of the mandible and three patients had osteonecrosis of the maxilla. In all patients pain was the presenting symptom, whereas patients who had prior dental extraction or artificial dentures had also purulent discharge. In two patients who had not had previous dental extraction or dentures, destabilization of their teeth occurred. In 13 patients dental extraction within the last year preceded the diagnosis of osteonecrosis, two patients had dentures, and two patients had no prior procedures in the oral cavity. Diagnosis was clinical in 11 patients, whereas biopsy was obtained in six patients to exclude metastatic disease. Necrotic bone was the only histologic finding, with surrounding bacteria but no evidence of bacterial invasion in the area of necrosis. Bisphosphonate infusions were discontinued after the confirmation of diagnosis. Management of all patients was conservative. Only minor debridement procedures were attempted to reduce sharp edges and trauma to surrounding tissues. All patients received multiple courses of antibiotics. The initial regimen contained amoxicillin or amoxicillin/clavulanate or metronidazole. Improvement of oral hygiene was recommended and oral rinses of chlorhexidine were prescribed. Measures were taken to reduce the contact of artificial dentures with the exposed bone.
Treatment with antibiotics resulted in transient improvement, but only one patient showed sustained improvement of osteonecrosis after multiple courses of antibiotics. The other 16 patients had persistent disability, mainly consisting of recurrences with purulent discharge and pain after the discontinuation of the antibiotics. One patient received hyperbaric oxygen without improvement. The minimum follow-up after the development of osteonecrosis has been 4 months (range, 4 to 24 months) and the lack of symptomatic or radiologic improvement in these 16 patients indicates that bone defects are permanent.
DISCUSSION
Osteonecrosis refers to the death of the bone as a result of impaired blood supply to the affected areas. Cancer and its treatment have been described as risk factors for the development of osteonecrosis.16 The most common site of osteonecrosis is the femoral head. Avascular ONJ has been associated predominantly with radiation of the head and neck, known as osteoradionecrosis,17 but has also been described after chemotherapy.18,19 Recently, ONJ has been reported after treatment with the bisphosphonates pamidronate and zoledronic acid in cancer patients.8-15 Although these reports make the association of bisphosphonate and the development of ONJ likely, the true incidence of osteonecrosis is unknown. The first attempt to determine true incidence was reported by Durie et al,10 who performed a Web-based survey in 1,203 patients with MM and breast cancer receiving bisphosphonates. Some limitations of the study include the fact that the diagnosis of ONJ was based on the answers given by the patients and that patients with dental problems might have been more responsive to the survey. We attempted to overcome this problem by prospectively studying the development of osteonecrosis during the last 2 years. This is the first analysis using this methodology; we believe this method overcomes some of the limitations of the previous reports and provides a denominator for the development of ONJ. Furthermore, our analysis is the first to include all types of cancer patients and thus provides the opportunity to assess possible differences among different primary sites. A limitation, common for all reports up to now, is its retrospective nature. Retrospective studies are subject to biases, the most important of which may have been introduced by the increased awareness of this adverse effect after 2003. We attempted to minimize that effect by selecting patients based on the time of exposure of patients with documented ONJ. We cannot exclude the possibility that a few patients before that time point may have been missed. Nevertheless, this number is likely to be small, given that ONJ causes intense symptoms, which cannot remain unrecognized.
The incidence of osteonecrosis in MM patients was 9.9% and the incidence in breast cancer patients was 2.9%, which are slightly different from those of Durie et al10 for documented osteonecrosis (6.8% and 4.4%, respectively). The difference in the incidence between myeloma and breast cancer in our series is not significant and is most probably due to the different time of exposure between these groups. Indeed, our analysis indicated that the time of exposure to the drug and the number of infusions are the most significant risk factors for development of osteonecrosis. None of our patients who received fewer than 12 bisphosphonate infusions has developed ONJ, whereas the median exposure to the drug for patients who developed ONJ was almost twice that of patients who did not. Similar observations have been reported in abstract form by Durie et al.20 Our analysis suggested a continuous increase in the incidence even after 5 years of exposure. Nevertheless, these results should be viewed with caution because of the small number of patients who have had such long exposure.
The type of bisphosphonate may play a role in the development of ONJ. This complication has been described exclusively after exposure to nitrogen-containing bisphosphonates pamidronate and zoledronic acid. Furthermore, Durie et al10 suggested that the risk is higher with zoledronic acid than with pamidronate. The difference between the two types of bisphosphonates is even sharper in our study. We did not observe any occurrences of ONJ with pamidronate alone, although there were nine occurrences among 69 patients (13%) treated with pamidronate and zoledronic acid sequentially. The difference in the hazard between zoledronic acid and pamidronate plus or minus zoledronic acid was significant, indicating that the development of ONJ occurs earlier with treatment with zoledronic acid. The reason for this difference is unknown. A possible explanation is the more potent inhibitory effect of zoledronic acid on bone turnover compared with pamidronate. Pamidronate is approximately 100- to 700-fold more potent than etidronate, whereas ibandronate and zoledronic acid show 10,000- to 100,000-fold greater potency than etidronate.21 Furthermore, zoledronic acid produced a greater reduction of collagen type-I degradation products (N-telopeptide) than pamidronate in a recent study,22 confirming the stronger antiresorptive activity of zoledronic acid. Thus, we may assume that the continuous, potent decrease in bone turnover caused by zoledronic acid may lead to increased bone fragility in the long run and, in combination with other local factors that are present in the jaw, to the development of ONJ.
Impaired blood supply has been implicated in the development of ONJ.23 There have been several reports indicating that zoledronic acid has antiangiogenic activity.24-26 This might explain its association with ONJ and the difference compared with pamidronate, the antiangiogenic properties of which are less established. We also studied the effect of thalidomide, an effective antimyeloma agent27 with antiangiogenic properties. We found no association of thalidomide use with the development of ONJ.
None of our patients who received ibandronate alone developed osteonecrosis. Ibandronate has only been approved recently for bone metastases from breast cancer and, thus, a longer follow-up is required until its association with ONJ can be accurately assessed.
Apart from time of exposure and type of bisphosphonates, corticosteroids and chemotherapy have been implicated in the development of ONJ.16,18,19,28 Most patients who developed osteonecrosis had been treated with one or both. Nevertheless, one patient with renal cancer had never received either corticosteroids or chemotherapy, whereas five patients had never received corticosteroids. Because of the diversity of the chemotherapy regimens and the timing of administration, it was impossible to perform an analysis addressing the contribution of this factor in the development of ONJ. Similarly, there was considerable diversity regarding the use of corticosteroids among the patients included in our study. The contribution of corticosteroids in the development of bisphosphonates-induced ONJ should be addressed in properly designed studies. It has been speculated that dental procedures may be the precipitating factor,8,10,11 as indeed was the case for most of our patients. Nevertheless, no dental procedures or use of dentures were reported in two patients.
We conclude that ONJ is a complication that is correlated with long-term use of bisphosphonates; this complication has received much publicity and developed much controversy recently.29,30 This might have implications in the current standards of use of these drugs in cancer patients. The American Society of Clinical Oncology guidelines for MM31 and breast cancer32 suggest that bisphosphonates should be administered "until there is evidence of a substantial decline in the patient's general performance status." Taking into consideration the natural history of these diseases, this could result in administration of bisphosphonates to some patients for several years. Nevertheless, the studies on which current guidelines were based usually administered bisphosphonates for a maximum of 2 years.7,33-35 In view of the data reported by us as well as by others,10,15,19 caution is required for use of pamidronate and zoledronic acid beyond 2 years. Furthermore, patients should improve their oral hygiene, whereas oncologists and dentists should be aware of this complication and its management. This is also emphasized by new postmarketing guidelines issued for pamidronate and zoledronic acid.36 Reinitiating bisphosphonate therapy in patients suffering from osteonecrosis is debated and warrants additional study. Prospective randomized studies are needed to assess the incidence of ONJ and the safety of bisphosphonates in cancer patients.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
NOTES
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Package Insert Revisions re: Osteonecrosis of the jaw: Zometa (zoledronic acid) injection and Aredia (pamidronate disodium) injection. Oncologic Drugs Advisory Committee Meeting, March 4, 2005. http://www.fda.gov(Aristotle Bamias, Efstath)