A case series and review of canine idiopathic osteonecrosis of the jaw

Osteonecrosis of the jaw (ONJ) risk in breast cancer patients after zoledronic acid treatment

Dental Extractions in Patients Receiving Bisphosphonate Therapy

9052 Background: Osteonecrosis of the jaw (ONJ) is a serious long-term effect of intravenous bisphosphonates. We report characteristics of patients with ONJ at Roswell Park Cancer Institute (RPCI) and utility of bone scans in its diagnosis. Methods: Patients were identified using RPCI database. ONJ diagnosed was staged using the system used for jaw osteoradionecrosis (Schwartz et al, Am J Clin Oncol, 2002). Controls included patients receiving bisphosphonates between July 2002 and 2006. Routine whole body bone scans were reviewed for jaw uptake. Statistical analysis was done using SAS 9.1. Results: Three hundred and fifty-four patients received intravenous bisphosphonates between July 2002 and 2006. Twenty-four (7%) were diagnosed with ONJ. Among patients with ONJ, fifteen (63%) had breast cancer, eight (33%) had multiple myeloma and one (4%) had lung cancer. Mean age was 56.8 years. (SD= 9.1) Thirteen patients (54%) had tobacco use, five (21%) had diabetes, nine (37.5%) had hypertension and twenty-three patients (96%) received chemotherapy. Five patients (21%) had caries, three (12.5%) had dental surgery, nine (37.5%) had periodontal disease, thirteen (54%) had extractions and one (4%) had prior dental trauma. Twenty-two patients (92%) presented with pain. Twelve patients (50%) had ONJ Stage 1, eight (33%) Stage 2 and four (17%) Stage 3. Median duration of exposure to bisphosphonates was 39 months. The difference between the average number of infusions in the ONJ group (11.2, CI: 11.3, 20.3) and control group (7.2, CI: 6.2, 8.2) was found to be significant (p<0.0009). Three patients (12.5%) had progressive ONJ. Thirteen patients with ONJ had bone scans and twelve (92%) showed jaw uptake. Among controls, one hundred and eighty-three had bone scans and one hundred and twenty-eight (70%) showed jaw uptake. This difference was not significant. (p=0.114, two-tailed Fisher's exact test). Conclusions: In our study, chemotherapy, smoking, prior dental extractions and the number of bisphosphonate infusions appear to be risk factors for ONJ. It has been recently reported (Chiandussi et al., Dentomaxillofacial Radiol. 2006) that bone scans can be used as a screening tool for ONJ, however, in our series jaw uptake on bone scan was not a reliable predictor for the development of ONJ. No significant financial relationships to disclose.

A Review of the Literature on Osteonecrosis of the Jaw in Patients with Osteoporosis Treated with Oral Bisphosphonates: Prevalence, Risk Factors, and Clinical Characteristics

骨質疏鬆患者接受口服雙磷酸鹽類藥物併發顎骨壞死：流行病學、藥物動力學及藥物基因體學

Making a Case for Defining Osteonecrosis of the Jaw

552 Background: Bisphosphonates reduce the risk of bone metastases in postmenopausal women with early-stage breast cancer but carry the risk of osteonecrosis of the jaw (ONJ). We used the data collected in the S0307 trial to describe factors associated with provoked and unprovoked ONJ. Methods: In S0307, 6097 patients with Stage I-III breast cancer who had surgery were randomized to receive zoledronic acid (ZA) 4mg IV monthly for 6 months, then every 3 months, clodronate (CL) 1600mg daily, or ibandronate (IB) 50mg daily for three years, with no difference in bone metastases or disease-free survival. Patients completed dental procedures prior to and had a dental exam at enrollment. Pearson’s Chi-squared and Student’s T-test were used to test differences in categorical and continuous variables, respectively; logistic regression was used test independent association. Results: Of 5836 evaluable women, 48 developed ONJ, which was associated with bisphosphonate type (28/2124 (1.26%) for ZA, 8/2185 (0.36%) for CL and 12/1527 (0.77%) for IB (p = 0.002). Median time to onset of ONJ was 24.9 (1.4-66.6) for ZA, 41.2 months (range 33.8-67.4) for CL, 23.9 (2.1-75.3) for IB (p = 0.0447). Infection was present in 21 (43.8%) and absent in 20. ONJ was considered unprovoked in 20 (41.7%) and provoked by dental extraction in 20 (41.7%), periodontal disease in 14 (29.2%), denture trauma in 6 (12.5%), other dental surgery in 3 (6.3%). ONJ was associated with dental calculus (OR 2.03 (95% CI: 1.08-3.81), gingivitis (OR 2.11, 95% CI: 1.12-3.98), and periodontal disease (OR 2.87, 95% CI 1.45-5.53) that were moderate/severe and > 4mm periodontitis (OR 2.20, 95% CI 1.18-4.08). Patients with provoked and unprovoked ONJ had similar amounts of dental disease and lesion location. ONJ was not associated with dentures, plaque, chemotherapy, corticosteroids or renal adverse events. In multivariate analysis (limited by small sample), only bisphosphonate type was associated with ONJ. Conclusions: ONJ prevalence was low, likely due to patients completing dental procedures before enrollment. ZA carried a higher risk of ONJ (though current adjuvant dosing interval recommendations are less frequent), with time to onset similar to IB. Oral CL and IB (not currently available in the United States) are thus likely more appropriate for patients with poor dental health. Clinical trial information: NCT00127205.

Osteonecrosis: a multifactorial etiology.

BackgroundMediatization of bisphosphonate(BP)-related osteonecrosis of the jaw (ONJ) has hampered the treatment of osteoporosis (OP). The risk of ONJ associated with oral BP in OP and zoledronate (ZOL) in oncology...

Osteonecrosis of the jaw (ONJ) is a well-known devastating side effect of bisphosphonate therapy for cancer. Several ONJ cases of patients using oral bisphosphonates have been reported in the literature. The present study analyzed the clinical features, predisposing factors, and treatment outcome of 11 patients with oral bisphosphonates-related ONJ. Osteonecrosis of the jaw (ONJ) is a well-known side effect of parenteral bisphosphonates therapy. Although ONJ has been reported in patients using oral bisphosphonates, documentation of this entity is sparse. It was hypothesized that the clinical features, predisposing factors, and treatment outcome of this population are different from those of oncologic patients. This retrospective bi-central study involved 98 ONJ patients, 13 of whom were treated with oral bisphosphonates. Two patients were excluded because of previous use of intravenous bisphosphonates. The profiles of 11 patients were analyzed. The mean duration of alendronate use before developing ONJ was 4.1 years. ONJ was triggered by dental surgery in 9 patients and by ill-fitted dentures in 2. Heavy smokers were the most recalcitrant subjects. Among the nine patients with at least 6 months of follow-up, ONJ healed completely in three, partially in four, and not at all in two. ONJ is a rare devastating side effect of oral bisphosphonates associated with patient morbidity and high financial burden. Clinicians must be aware of this entity and inform patients of the risks of dental surgery. The synergistic effect of smoking in the pathogenesis of ONJ should be further investigated.

Osteonecrosis of the jaw and bevacizumab therapy.

To the Editors: We read with considerable interest the article by Raje et al. (1) shedding light on clinical, radiographic, and biochemical markers concerning biphosphonate osteonecrosis of the jaw (ONJ). The investigators highlight that most information regarding ONJ has been from case series and case reports (1). This was correct until recently as we reported the first pair-matched case-control study addressing potential risk factors for ONJ development in breast cancer patients under zolendronic acid medication (2).Raje et al. (1) report that 7 of 11 patients did undergo tooth extraction. They do not, however, comment on tooth extractions as a potential risk factor. In our study, we report tooth extraction as the most potent ONJ predictor. Moreover, a recent article provides evidence that mucosal wound healing following tooth extractions could be actually defective, also showing that apoptosis is unlikely to be the key mechanism for keratinonocyte damage caused by biphosphonates (3).Another issue pointed out by Raje et al. (1) concerns ONJ incidence differences in the Greek and US populations. This could hardly be attributable to more tooth extractions in the Greek population probably because of poor hygiene (4); thus, it could be an issue of differential susceptibility to ONJ in the Greek population. Susceptibility differences could exist, given that we reported decreased susceptibility to adenocarcinoma among Greek patients with Barrett's esophagus and inflammatory bowel disease, perhaps attributable to Bax-protein overexpression (5).Raje et al. (1) point out that two studies from Greece suggest zolendronic acid medication might be an independent risk factor for ONJ development. Zolendronic acid is considered the most potent osteoclast inhibitor (2), and in our institution, we have witnessed more ONJ in patients receiving zolendronic acid rather than other bisphosphonate treatment. Hitherto, we are monitoring this variable in a cohort study (2). Pharmacogenomics is a promising field in cancer treatment and the investigators conclude (3) that clinical and laboratory end points will be validated in future prospective clinical trials (1). This is very true, but to our point of view, more attention should be paid in prevention of ONJ, if possible via simple risk predictors. In this regard, we have shown that ONJ is associated with tooth extraction and use of overdentures, currently updating the American Society of Clinical Oncology's level of evidence from V to III (2). We therefore concluded, based on evidence, that oncologists should refer their patients for baseline dental evaluation and potential pretreatment before engaging bisphosphonate therapy (2). Evidence provided by Raje et al. (1) shedding light on the pathophysiologic basis of the above association strengthens our point.No potential conflicts of interest were disclosed.

Aim: The use of bisphosphonates (BP) has been linked to the development of an osteonecrosis of the jaw (ONJ). This doctoral dissertation initially aimed to clinically describe this new disease. Then followed an epidemiologic analysis of BP prescription in Germany. Based on that, the major goal was to identify individual risk factors towards an ONJ among patients with underlying malignancies or osteoporosis. Methods: A register (Register) for all cases of ONJ in Germany was installed at the Charite University Hospital and between 2005-2012, a total of 1229 cases were collected. Epidemiological information on BP use were analyzed from insurance claims data in a joint project with the University of Bremen. The Register itself served for detailed analysis of clinical aspects and to compare the duration of BP-treatment until an ONJ occurred for the different BPs and the various underlying diseases. If possible, all analyses were stratified by gender and age. Results: Approximately 0.1% of the German public was treated with an i.v. BP per year. Men received i.v. BPs more often, but those under treatment died significantly earlier than women. An ONJ occured after a median i.v. treatment time of 25 months. Ibandronate and Zoledronate users suffered from their ONJ significantly earlier than Pamidronate users. A sequential intake of two different BPs could significantly prolong treatment time. Age and a concomitant osteoporosis had no influence on treatment duration. In comparison to epidemiological data, the Register showed an unexpected accumulation of women, patients with multiple myeloma, and those treated with Zoledronate. Dental anamnesis showed a tooth extraction under BP-treatment in 67% of patients but 11% developed their ONJ spontaneously. The ONJ-free survival was poorest for patients with kidney cancer. Gender appears to be an additional risk factor for males in that subgroup. The incidence of an ONJ for patients with osteoporosis was 0,001%. Conclusion: Life expectancy influences the duration of BP treatment and, hence, raises the chance of developing an ONJ. How soon an ONJ occurs depends on various risk factors such as the type of the underlying disease, the type and application of the BP, and sometimes on gender. The information gained from this doctoral thesis will help doctors to individually advise their patients on the risk to develop an ONJ under BP-treatment.

Osteonecrosis of the jaws is associated with high-dose bisphosphonate treatment in patients with cancer

19594 Background: ONJ has been associated with IV bisphosphonate use in cancer patients (pts) and chemotherapy may be an additional risk factor. ONJ is believed to result from localized vascular insufficiency due to faulty bone remodeling. ONJ incidence in pts not receiving chemotherapy (e.g. Paget's disease) is reportedly only 0.8%; prostate cancer pts have an incidence of 6.5%. Methods: We reviewed data from pts with advanced AIPC who developed ONJ while being treated on a Phase II study of ATTP. Results: Six of 36 (17%) pts treated with ATTP had ONJ confirmed by oral surgery. Four of the 6 pts presented with pain and, in five, the ONJ was mandibular in location. All pts were treated conservatively with either sequestrectomy or oral cleansing with chlorhexidine. All pts had been treated monthly with IV zoledronic acid (ZA). The mean duration of ZA use before diagnosis of ONJ was 20 months (mos). One patient had been treated with oral alendronate for 3 years and then developed ONJ after 5 mos of ZA. Of the 36 pts on-study, previous dental history could be verified in 24 pts. ONJ was diagnosed in 4 of the 5 pts with a prior dental infection or invasive dental procedure. Pts received an average of 11 cycles of ATTP before ONJ was diagnosed. All pts with ONJ had received full doses of bevacizumab and most had received full doses of all medications for all cycles. Conclusions: The possibility exists that the risk for ONJ may be higher with specific chemotherapy regimens, particularly those that include steroids or anti-angiogenic agents. However, at this time prior dental infections or procedures remain the greatest known risk factor. It is also possible that the relatively high incidence of ONJ in prostate cancer patients may reflect increased awareness in this population. Randomized phase III trials in AIPC, specifically addressing the incidence of ONJ, are needed to determine whether specific chemotherapy regimens are associated with an increased risk of this complication. No significant financial relationships to disclose.