The phenomenon of osteonecrosis of the jaw in patients with metastatic breast cancer

Osteonecrosis of the jaw (ONJ) has been noted to occur in patients with cancer receiving bisphosphonate therapy and may also be referred to as bisphosphonate associated osteonecrosis (BON). ONJ has come to attention through case reporting and the pathogenesis and true incidence of this condition are not yet defined. ONJ appears to be a relatively uncommon event, but it is of clinical significance; the evolving data on ONJ are discussed here.     

Incidence of bisphosphonate‐associated osteonecrosis of the jaws in breast cancer patients

BACKGROUND:

Bisphosphonate‐associated osteonecrosis of the jaws (BP‐ONJ) is a relatively new disease. The aim of this study was to evaluate the prevalence of BP‐ONJ in breast cancer patients with osseous metastasis and bisphosphonate therapy.

METHODS:

A retrospective study was conducted in a EUSOMA accredited breast unit in Germany. All patients treated from January of 2000 to March of 2006 with metastatic breast cancer and bisphosphonate therapy were reviewed. All patients were contacted, and missing data were completed through structured interviews with their dentists and physicians (n = 75). Primary outcome was the development of BP‐ONJ and the detection of possible additional trigger factors for the development of BP‐ONJ.

RESULTS:

A total of 117 patients with breast cancer fulfilled the inclusion criteria, and data for 75 still living patients were included. Of these 75, 4 patients developed a BP‐ONJ, resulting in a prevalence of 5.3%: 3 patients received zoledronate only; 1 patient had first pamidronate followed by zoledronate and ibandronate. A tooth extraction could be identified as an additional trigger factor for 2 patients.

CONCLUSIONS:

With a prevalence of 5.3%, BP‐ONJ in breast cancer patients has become a relevant disease that should be discussed with patients for whom bisphosphonates have been recommended. Appropriate dental care before bisphosphonate therapy commences has been advised to reduce the occurrence of BP‐ONJ. Cancer 2009. © 2009 American Cancer Society.     

Osteonecrosis of the jaw in cancer patients receiving IV bisphosphonates

Cases of osteonecrosis of the jaw (ONJ) have been reported with an increasing frequency over the past few years. ONJ is most often identified in patients with cancer who are receiving intravenous bisphosphonate therapy but it has also been diagnosed in patients receiving oral bisphosphonates for nonmalignant conditions. The condition involves exposed bone of the maxilla or mandible. Although it is often associated with a recent dental surgical procedure, spontaneous ONJ can also occur. Patients commonly present with symptoms. Through case reporting and clinical experience, there is a suggestion that the incidence of ONJ in patients with cancer receiving intravenous bisphosphonates ranges between 1% and 10%. Management of ONJ focuses on maximizing oral health, conservative actions with mouth rinses, antibiotics, and avoidance of unnecessary invasive dental procedures. The currently available data on ONJ are reviewed here.     

Osteonecrosis of the maxilla and mandible in patients with advanced cancer treated with bisphosphonate therapy

Cases of osteonecrosis of the jaw (ONJ) have been reported with an increasing frequency over the past 5 years. ONJ is most often identified in patients with cancer who are receiving intravenous bisphosphonate (IVBP) therapy, but it has also been diagnosed in patients receiving oral bisphosphonates for nonmalignant conditions. To further categorize risk factors associated with ONJ and potential clinical outcomes of this condition, we performed a retrospective study of patients with metastatic bone disease treated with intravenous bisphosphonates who have been evaluated by the Memorial Sloan-Kettering Cancer Center Dental Service between January 1, 1996 and January 31, 2006. We identified 310 patients who met these criteria. Twenty-eight patients were identified as having ONJ at presentation to the Dental Service and an additional 7 patients were subsequently diagnosed with ONJ. Statistically significant factors associated with increased likelihood of ONJ included type of cancer, duration of bisphosphonate therapy, sequential IVBP treatment with pamidronate followed by zoledronic acid, comorbid osteoarthritis or rheumatoid arthritis, and benign hematologic conditions. Our data do not support corticosteroid use or oral health as a predictor of risk for ONJ. Clinical outcomes of patients with ONJ were variable with 11 patients demonstrating improvement or healing with conservative management. Our ONJ experience is presented here.     

Patients with bisphosphonates-associated osteonecrosis of the jaw have reduced circulating endothelial cells

Osteonecrosis of the jaws (ONJ) associated with the use of bisphosphonates is a newly described entity. To elucidate the mechanism leading to ONJ and to test the hypothesis that in patients with ONJ the bisphosphonates may interfere with endothelial cell proliferation, using flow cytometric analysis we evaluated the number of circulating endothelial progenitor cells (EPCs) and circulating endothelial cells (CECs) in eight patients with bisphosphonate treatment and osteonecrosis, eight multiple myeloma (MM) patients with bisphosphonates treatment without ONJ and five normal subjects. MM patients showed an increase of CD34+ cells with respect the control subjects and ONJ subjects. EPCs and CECs were higher in MM patients compared to controls and ONJ patients. ONJ patients showed a decrease of EPCs compared to control subjects while CECs were similar to the controls group. Our results seem to show the possibility that bisphosphonates could have a antiangiogenic effect and a suppressive effect on CECs of patients with ONJ.     

Osteonecrosis of the jaw in patients with bone metastases treated with bisphosphonates: a retrospective study

OBJECTIVE: Bone metastases are a major cause of morbidity in cancer patients. Treatment includes bisphosphonates, which are also associated with avascular osteonecrosis of the jaw (ONJ). Our aim was to evaluate the correlation between bisphosphonates and ONJ. PATIENTS AND METHODS: Of the 539 patients with bone metastases treated in our department from June 2002 to December 2006 with i.v. bisphosphonates, eight (1.5%) developed ONJ. RESULTS: The eight patients with ONJ had all been given zoledronic acid, and two had also been treated with pamidronic acid. In four of the patients, ONJ was diagnosed during treatment, while in the remaining four it was diagnosed several months after therapy with bisphosphonates had ended. Six of these patients received local noninvasive treatment, of whom five progressed. Two showed apparent autolimitation of the disease. The remaining two patients underwent surgical resection and currently show no signs of relapse. All eight ONJ patients presented with various concomitant risk factors such as paradontopathy, dental extraction, or spontaneous avulsion. CONCLUSIONS: Our results show that ONJ can appear months after interruption of treatment and that a surgical approach can be used in suitable cases. Closer cooperation is needed among specialists to define guidelines for the prevention of ONJ in patients with bone metastases.     

Osteonecrosis of the jaw: dental outcomes in metastatic breast cancer patients treated with bisphosphonates with/without bevacizumab

The etiology, optimal management, and outcome of osteonecrosis of the jaw (ONJ) are not well understood. Because healing after mucosal trauma requires revascularization, theoretically, the combination of bevacizumab (bev) and a bisphosphonate (BP) could affect the time to development of ONJ and/or the response to dental therapy. We reviewed all cases of ONJ in metastatic breast cancer patients treated at our institution with bev+BPs and BPs alone between October 2002 and April 2010. We identified 27 ONJ patients with a median age of 57 years (range, 40 to 68 years). Seven patients received bev+BPs; 20 patients received BPs alone. Patients received intravenous zolendronate (95%), pamidronate (20%), or both (15%). Patients were treated with antibiotics (93%), alveoplasty/debridement (67%), and chlorhexidine scrub (81%). There was no difference in dental treatment between the groups or by the year of diagnosis (before 2007 versus 2007-2010). Complete resolution (CR) was achieved in 24% of all patients; 33% treated with bev+BPs, and 21% treated with BPs alone. Rates of CR improved from 15% to 33% after 2007. The median time to response was 5.6 months (range, 1.3 to 67.5 months). The addition of bev to BPs did not appear to alter the time to development of ONJ (32.6 months versus 34.6 months, respectively). The number of BP treatments administered before the diagnosis of ONJ between bev+BPs and BPs (32 doses versus 36.5 doses) was similar. However, our sample size was too small to characterize the difference statistically. Because dental management of ONJ has not changed over time at our institute, early recognition and screening may account for the improvement in dental outcomes.     

Bisphosphonates and osteonecrosis of the jaw: cause and effect or a post hoc fallacy?

BACKGROUND: An increasing amount of reports are being published suggesting a relationship between the use of bisphosphonates (BPs) and the development of osteonecrosis of the jaw (ONJ). We reviewed the currently available evidence and explore the potential mechanisms of action based on the known effects of the concerned BP. DESIGN: The MEDLine, Current Contents and Science Citation Index Expanded databases were queried and the results augmented by analyzing cited references and recent congress proceedings. RESULTS: 22 papers were included detailing 225 patients, all based on retrospective chart review without control groups. The prevalence of ONJ was estimated at 1.5%. The involved BPs were pamidronate, zoledronic acid, alendronate and risedronate, all potent nitrogen-containing agents. The most common symptom was pain (81.7%), although 12.2% of cases were asymptomatic. In 69.3% of patients ONJ was preceded by a dental extraction. At the time of diagnosis, 74.5% of patients were receiving chemotherapy and in 38.2% of cases corticosteroids were administered. Although various conservative and surgical treatment modalities were reported, residual sites of ONJ persisted in 72.5% of cases. CONCLUSION: Although not enough evidence is available to prove a causal link, it seems that under specific circumstances local defenses can become overwhelmed resulting in ONJ.     

Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates: definition and management of the risk related to zoledronic acid

PurposeBisphosphonates (BPs) are currently used to treat bone lesions in patients with multiple myeloma (MM). Osteonecrosis of the jaw (ONJ) has been reported as an adverse event of such treatment, especially after treatment with zoledronic acid (ZA). The aim of this study was to evaluate incidence, risk factors, management, and prevention strategies of ONJ in order to optimize the current standard use of BPs in MM.Patients and MethodsWe reviewed the medical records of 105 patients with MM treated in 2 hematology departments with monthly pamidronate 90 mg and/or ZA 4 mg and evaluated for ≥ 12 months. Because they are risk factors for ONJ development, we analyzed patient and disease features, previous MM treatments, type and number of BP infusions, and previous history of dental procedures.ResultsSeventeen patients (16%) with MM treated with BPs developed ONJ after a median number of 43 BP infusions (vs. 28 in patients without ONJ; P = .035). In 11 of 17 patients, ONJ arose after a tooth extraction. Among risk factors, the administered doses of ZA were significantly associated with ONJ, and 12 consecutive doses of ZA proved to double the risk of developing this complication. Regular hard- and soft-tissue oral assessment was of benefit in the prevention of further ONJ occurrence.ConclusionThe most important risk factor for ONJ is represented by the number of ZA infusions. Tooth extractions and invasive procedures should be avoided. A multidisciplinary approach including oncohematologists and dental teams proved critical to better identify, prevent, and manage ONJ.     

Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors.

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.     

Bisphosphonate-induced differential modulation of immune cell function in gingiva and bone marrow in vivo: Role in osteoclast-mediated NK cell activation

The aim of this study is to establish osteoclasts as key immune effectors capable of activating the function of Natural Killer (NK) cells, and expanding their numbers, and to determine in vivo and in vitro effect of bisphosphonates (BPs) during NK cell interaction with osteoclasts and on systemic and local immune function. The profiles of 27 cytokines, chemokines and growth factors released from osteoclasts were found to be different from dendritic cells and M1 macrophages but resembling to untreated monocytes and M2 macrophages. Nitrogen-containing BPs Zoledronate (ZOL) and Alendronate (ALN), but not non-nitrogen-containing BPs Etidronate (ETI), triggered increased release of pro-inflammatory mediators from osteoclasts while all three BPs decreased pit formation by osteoclasts. ZOL and ALN mediated significant release of IL-6, TNF-` and IL-1β, whereas they inhibited IL-10 secretion by osteoclasts. Treatment of osteoclasts with ZOL inhibited NK cell mediated cytotoxicity whereas it induced significant secretion of cytokines and chemokines. NK cells lysed osteoclasts much more than their precursor cells monocytes, and this correlated with the decreased expression of MHC class I expression on osteoclasts. Intravenous injection of ZOL in mice induced pro-inflammatory microenvironment in bone marrow and demonstrated significant immune activation. By contrast, tooth extraction wound of gingival tissues exhibited profound immune suppressive microenvironment associated with dysregulated wound healing due to the effect of ZOL which could potentially be responsible for the pathogenesis of Osteonecrosis of the Jaw (ONJ). Finally, based on the data obtained in this paper we demonstrate that osteoclasts can be used as targets for the expansion of NK cells with superior function for immunotherapy of cancer.     

Bevacizumab and osteonecrosis of the jaw: incidence and association with bisphosphonate therapy in three large prospective trials in advanced breast cancer

Long-term bisphosphonate therapy is associated with increased risk of osteonecrosis of the jaw (ONJ). In a retrospective analysis, a 16% ONJ incidence was reported in patients receiving bisphosphonates with anti-angiogenic therapy (bevacizumab or sunitinib) for bone metastases from breast, colon, or renal cell cancers. To assess ONJ incidence with bevacizumab, we analysed data from 3,560 patients receiving bevacizumab-containing therapy for locally recurrent or metastatic breast cancer (LR/MBC) in two double-blind, randomised trials (AVADO and RIBBON-1) and a large, non-randomised safety study (ATHENA). The overall incidence of ONJ with bevacizumab was 0.3% in the blinded phase of the two randomised trials and 0.4% in the single-arm study. There was a trend towards increased ONJ incidence in patients who received bisphosphonate therapy versus those with no bisphosphonate exposure (0.9 vs. 0.2%, respectively, in the pooled analysis of the randomised trials; 2.4 vs. 0%, respectively, in ATHENA). In conclusion, this is the largest analysis of ONJ in patients receiving bevacizumab for LR/MBC. The 0.3–0.4% incidence is considerably lower than previously suggested with anti-angiogenic therapy in a small retrospective analysis. The risk of ONJ appeared to be increased in patients exposed to bisphosphonates, a pattern consistent with observations before the introduction of anti-angiogenic therapy to breast cancer management. The 0.9–2.4% incidence seen in bisphosphonate-exposed patients receiving bevacizumab is within the 1–6% range reported for bisphosphonates alone. Good oral hygiene, dental examination, and avoidance of invasive dental procedures remain important in patients receiving bisphosphonates, irrespective of bevacizumab administration.     

Correlation of macrophage-mediated tumor-cell lysis with the production of macrophage cytolytic factor (CF). Preliminary characterization of a factor inhibiting CF production

Macrophage-mediated cytolysis of thymidine-prelabelled murine A9 fibrosarcoma cells was compared to the level of cytolytic factor (CF) present in the cultures by assaying supernatant aliquots on actinomycin (AcD)-treated A9 fibrosarcoma cells. A good correlation between the level of A9 killing and CF titer was observed when different concentrations of lipopolysaccharide (LPS) were added to various macrophage populations: murine peritoneal cells, short-term bone-marrow (BM)-derived macrophages and JBM phi macrophage lines. Optimal A9 killing and CF secretion, equivalent to the killing of about 1000 AcD-pretreated A9 cells by a single macrophage, were obtained following activation of JBM phi by LPS. CF production by BM-derived macrophages was enhanced in serum-free medium when compared to its release in the presence of fetal calf serum. The LPS-activated macrophages could be restimulated by the activating agent to produce CF following one week of propagation in the absence of LPS. On the other hand, CF activity was absent from the supernatants of activated macrophages co-cultured with normal embryonic fibroblasts, which are resistant to macrophage-mediated killing. This effect could be attributed to a factor, secreted by normal fibroblasts but not by A9 cells, which suppressed CF release from the activated macrophages. Our data strongly support earlier observations, suggesting that CF [which appears to resemble the tumor necrosis factor (TNF)] is responsible for LPS-induced macrophage-mediated tumor cell lysis. It is suggested that suppression of the latter process by the fibroblast-derived factor proceeds via inhibition of CF/TNF production from the macrophage.     

Effect of recombinant tumor necrosis factor on tumoricidal activation of murine macrophages: synergism between tumor necrosis factor and gamma-interferon

The activation of tumoricidal murine macrophages by recombinant human tumor necrosis factor (rH-TNF) alone or in combination with recombinant murine gamma-interferon (rM-IFN-gamma) was examined. When used alone, rH-TNF (10(-1)-10(5) units/ml) did not induce macrophage tumoricidal activity against TNF-insensitive P815 mastocytoma cells. Combining rH-TNF with rM-IFN-gamma resulted in the synergistic induction of tumoricidal activity in resident peritoneal macrophages. This synergistic effect was not due to contaminating bacterial lipopolysaccharide. A comparative study using recombinant murine tumor necrosis factor (rM-TNF) showed that rM-TNF alone also could not stimulate murine macrophages and there was no significant difference between effects of rM-TNF and rH-TNF on macrophage activation in the presence of rM-IFN-gamma. In experiments comparing sequential to simultaneous exposure of macrophages to rH-TNF and rM-IFN-gamma, it was found that: (a) when macrophages are primed with rM-IFN-gamma, rH-TNF serves only as a very weak triggering signal for tumoricidal activation; and (b) marked activation is obtained only when macrophages are exposed to the two cytokines simultaneously. These results suggest that TNF has an autocrine regulatory function in concert with lymphokines in macrophage-mediated host defense against tumors.     

Impact of dental care in the prevention of bisphosphonate-associated osteonecrosis of the jaw: a single-center clinical experience

BackgroundOsteonecrosis of the jaw (ONJ) is associated with bisphosphonate (BP) therapy and invasive dental care. An Interdisciplinary Care Group (ICG) was created to evaluate dental risk factors and the efficacy of a preventive restorative dental care in the reduction of ONJ risk.Patients and methodsThis prospective single-center study included patients with bone metastases from solid tumors. Patients who received at least one BP infusion between October 2005 and 31 August 2009 underwent one or more ICG evaluation and regular dental examinations. We also retrospectively evaluated patients with bone metastases from solid tumors who did not undergo dental preventive measures.ResultsOf 269 patients, 211 had received at least one infusion of BP therapy: 62% were BP naive and 38% had previous BP exposure. Of these 211 patients followed for 47 months, 6 patients developed ONJ (2.8%). Of 200 patients included in the retrospective analysis, 11 patients developed ONJ (5.5%).ConclusionsIn comparison with published ONJ rates and those extrapolated from the retrospective analysis, the observed ONJ rate in the prospective group was lower, suggesting that implementation of a preventive dental program may reduce the risk of ONJ in metastatic patients treated with i.v. BP therapy.     

Initial experience with conservative treatment in cancer patients with osteonecrosis of the jaw (ONJ) and predictors of outcome

Background: Overall survival (OS) and outcome of cancer patientswith bisphosphonate-associated osteonecrosis of the jaw (ONJ)using conservative treatment (chlorhexidine 0.12% rinse, intermittentantibiotics, and careful sequestrectomy) are unknown. Design: In all, 33 ONJ patients were studied for OS and ONJoutcome. Results: Median duration of bisphosphonate treatment was 27months (range 4–115) and was stopped in 25 (76%) patients.Nine (27%) cases presented with stage 1, 21 (64%) with stage2, and 3 (9%) with stage 3 disease. During median follow-upof 23 months, 11 patients (33%) died (median survival 39 months),with no ONJ-related fatalities. Out of 30 assessable patients,53% no longer had exposed bone, 37% had stable lesions, and10% showed progressive necrosis. The hazard ratio for healingwith doubling of bisphosphonate exposure was 0.419 [95% confidenceinterval (CI) 0.178–0.982; P = 0.045], stage 2 versusstage 1 disease 0.216 (95% CI 0.063–0.738; P = 0.015),and stage 3 versus stage 1 disease 0.084 (95% CI 0.008–0.913;P = 0.042). Cessation of bisphosphonate treatment did not influenceoutcome. Conclusions: Conservative treatment of ONJ leads to mucosalclosure in 53% of patients. Doubling the exposure time to bisphosphonatesand higher stages of ONJ significantly reduce ONJ healing rates. Key words: bisphosphonates, jaw, ONJ, osteonecrosis, outcome study Received for publication June 25, 2008. Revision received August 8, 2008. Accepted for publication August 11, 2008.     

Increased glioma growth in mice depleted of macrophages

Macrophages can promote the growth of some tumors, such as those of the breast and lung, but it is unknown whether this is true for all tumors, including those of the nervous system. On the contrary, we have previously shown that macrophages can slow the progression of malignant gliomas through a tumor necrosis factor-dependent mechanism. Here, we provide evidence suggesting that this antitumor effect could be mediated by T lymphocytes, as their number was drastically reduced in tumor necrosis factor-deficient mice and inversely correlated with glioma volume. However, this correlation was only observed in allogeneic recipients, prompting a reevaluation of the role of macrophages in a nonimmunogenic context. Using syngeneic mice expressing the herpes simplex virus thymidine kinase under the control of the CD11b promoter, we show that macrophages can exert an antitumor effect without the help of T lymphocytes. Macrophage depletion achieved by ganciclovir treatment resulted in a 33% increase in glioma volume. The antitumor effect of macrophages was not likely due to a tumoricidal activity because phagocytosis or apoptosis of glioma cells, transduced ex vivo with a lentiviral vector expressing green fluorescent protein, was rarely observed. Their antitumor effect was also not due to a destructive action on the tumor vasculature because macrophage depletion resulted in a modest reduction in vascular density. Therefore, this study suggests that macrophages can attenuate glioma growth by an unconventional mechanism. This study also validates a new transgenic model to explore the role of macrophages in cancer.     

Decreased occurrence of osteonecrosis of the jaw after implementation of dental preventive measures in solid tumour patients with bone metastases treated with bisphosphonates. The experience of the National Cancer Institute of Milan

Background: Screening of the oral cavity and dental care wassuggested as mandatory preventive measures of osteonecrosisof the jaw (ONJ) in patients receiving bisphosphonates (BPs).We investigated the occurrence of ONJ before and after implementationof dental preventive measures when starting BP therapy. Patients and methods: Since April 2005, 154 consecutive patientstreated with BPs (POST-Group) have undergone a baseline mouthassessment (dental visit ± orthopantomography of thejaws) to detect potential dental conditions and dental careif required. A retrospective review was also conducted of allconsecutive cancer patients with bone metastases (PRE-Group)and treated for the first time with BPs from January 1999 toApril 2005 in our clinic without receiving any preventive measure.Incidence proportion and incidence rate (IR) were used to estimatethe incidence of ONJ. Results: Among the study population (966 patients; male/female= 179/787), 73% had breast cancer. 25% of patients were givenzoledronic acid (ZOL), 62% pamidronate (PAM), 8% PAM followedby ZOL and 5% clodronate. ONJ was observed in 28 patients (2.9%);we observed a reduction in the incidence of ONJ from 3.2% to1.3%, when comparing—pre and post-implementation of preventivemeasures programme. Considering the patients exposed to ZOL,the performance of a dental examination and the applicationof preventive measures led to a sustained reduction in ONJ IR(7.8% in the PRE-Group versus 1.7% in the POST-Group; P = 0.016),with an IR ratio of 0.30 (95% confidence interval 0.03–1.26). Conclusions: ONJ is a manageable and preventable condition.Our data confirm that the application of preventive measurescan significantly reduce the incidence of ONJ in cancer patientsreceiving BPs therapy. Dental exams combined to the identificationof patients at risk in cooperation with the Dental Team canimprove outcomes and increase the number of ONJ-free patients. Key words: bisphosphonates, bone metastases, dental preventive measures, dental team, ONJ, osteonecrosis of the jaw, osteoporosis Received for publication February 15, 2008. Revision received June 17, 2008. Accepted for publication June 23, 2008.