Originally published as JCO Early Release 10.1200/JCO.2008.16.2768 on June 23 2008

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Bisphosphonate-Related Osteonecrosis of the Jaws: A Case-Control Study of Risk Factors in Breast Cancer Patients

Athanassios Kyrgidis, Konstantinos Vahtsevanos, Georgios Koloutsos, Charalampos Andreadis, Ioannis Boukovinas, Zisis Teleioudis, Anna Patrikidou, Stefanos Triaridis

From the Department of Oral Maxillofacial Surgery, 3rd Department of Clinical Oncology, and 2nd Department of Clinical Oncology, Theagenio Cancer Hospital; and 1st University Department of Otolaryngology, Aristotle University, AHEPA Hospital, Thessaloniki, Greece

Corresponding author: Kyrgidis Athanassios, MD, 3 Papazoli St, 546 30, Thessaloniki, Greece; e-mail: akyrgidi{at}dent.auth.gr, akyrgidi{at}gmail.com

	ABSTRACT

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Purpose Osteonecrosis of the jaws (ONJ) was initially described in 2001 in patients receiving intravenous bisphosphonate (BP) treatment. The objective of the present study was to determine whether routine dental procedures can be considered as possible risk factors for the development of ONJ in breast cancer patients receiving BP.

Patients and Methods Twenty breast cancer patients who developed ONJ receiving BP treatment were included in group A, whereas group B consisted of 40 matched controls (breast cancer patients who did not progress to ONJ receiving BP treatment). Routine dental care, smoking habits, history of tooth extraction, use of dentures, and root canal therapy were recorded.

Results Our results indicate that history of tooth extraction during zoledronic acid treatment (adjusted odds ratio [OR] = 16.4; 95% CI, 3.4 to 79.6) and the use of dentures (adjusted OR = 4.9; 95% CI, 1.2 to 20.1) increase the risk of developing ONJ.

Conclusion The outcome of the present study suggests early referral by oncologists for dental evaluation for every patient to be treated with BP. These results raise the current American Society of Clinical Oncology Level of Evidence linking certain dental procedures with ONJ from V to III. Further studies are needed to assess other possible risk factors and also to highlight the etiopathogenesis mechanism of ONJ.

	INTRODUCTION

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The skeleton is the most common site to be affected by metastatic disease in many types of cancer. Multiple myeloma, breast, and prostate cancer have the highest prevalence of bone metastases.¹ Although the overall survival and life span of patients with bone metastases is relatively long, they experience considerable morbidity as a result of skeletal-related events. These events include bone pain, general weakness/fatigue, impaired mobility, pathologic fractures, spinal cord compression, and hypocalcaemia, all of which contribute to an impaired quality of life.² Breast cancer has a high incidence of bone metastases; up to 73% of patients with advanced breast cancer have bone metastases on presentation.¹ The prognosis of breast cancer patients who develop bone metastases is considerably better than that for patients with metastases in visceral sites.¹

Palliative bone-targeted therapies are designed to treat bone pain, disability from cord compression, and pathologic fractures. There are several approaches to the treatment of bone metastases, including endocrine or cytotoxic anticancer treatment, external-beam radiotherapy, palliative surgery, analgesia, and bisphosphonates (BPs).² BPs have emerged as an integral tool in the prevention of skeletal-related events in metastatic cancer patients. BPs reduce excessive bone turnover, resulting in preservation of structure and mineralization of the bone. On the basis of these properties, BPs have become the treatment of choice for preventing skeletal complications in cancer patients with bone metastases.³ Although the proper zoledronic acid (ZA) treatment duration is yet to be established, currently available evidence suggests that bone morbidity is decreased for the period that the patient is receiving ZA treatment. According to clinical practice guidelines for breast cancer patients and multiple myeloma patients, ZA treatment should be continued until the appearance of treatment-related adverse events or until a substantial decline in patient performance status is observed.^4,5

Adverse effects associated with the use of BP are rare and consist of pyrexia, renal function impairment, and hypocalcaemia. Over the last few years, a new complication associated with the use of BP has been described, namely avascular osteonecrosis of the jaw (ONJ).⁶ Since 2003, more than 200 new patients with ONJ have been reported, most often multiple myeloma and breast cancer patients.³ An early report estimated the incidence of ONJ at 12.9% in patients receiving BP.⁶ In a prospective study by Bamias et al,⁷ the overall incidence of ONJ was estimated to be 6.7% (17 of 252 patients), whereas the incidence in multiple myeloma, breast cancer, and prostate cancer was reported to be 9.9%, 2.9%, and 6.5%, respectively. In a previous study from our institution, we reported the incidence to be 11.0% in 254 multiple myeloma patients receiving BP treatment.⁸

BP in general and especially ZA are thought to promote apoptotic signals in both osteoclasts and keratinocytes that reduce and destruct the immune keratinocyte barrier of oral mucosa. In a previous report from our institution, we have demonstrated that the combination of osteoclast and keratinocyte apoptosis is a possible pathway that leads to ONJ based on the observation that the osteonecrotic lesions were, in all patients, reported to involve only the attached gingiva.⁹ To date, no risk factors have been statistically correlated to ONJ progression. History of tooth extraction and use of dentures have been suggested as risk factors.⁷ In the present article, we investigate the possible link between ONJ and certain routine dental procedures performed during ZA treatment.

	PATIENTS AND METHODS

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In this retrospective case-control study, we included breast cancer patients with ONJ who were treated in our department to investigate possible risk factors for development of ONJ among routine dental procedures. All patients included in the study were treated for ONJ at the maxillofacial department of Theagenio Cancer Hospital (Thessaloniki, Greece) from October 2002 to October 2007. Details regarding their ambulatory visits and hospitalization days are reported in the results section. All patients received ZA treatment for a minimum of 6 months or longer. More specifically, ZA was intravenously (IV) administered in a single dose every fourth week. Thus, patients received approximately one dose per month. This is a common administration scheme for ZA.⁸ Detailed medical and dental records of treatment and follow-up appointments are kept at Theagenio Hospital for every patient receiving cancer treatment. All patients included in the study visited the hospital at least once monthly during the period they received multidisciplinary treatment. Because Theagenio Hospital does not have a dental department, all dental procedures were carried out outside of the hospital, typically in a private setting.

In group A of this study, we included patients who had been diagnosed with metastatic breast cancer and developed ONJ during treatment with intravenous BP. Criteria for inclusion in the study were age more than 18 years, diagnosis of breast cancer, clinically and radiographically diagnosed bone metastases, ZA treatment for a minimum period of 6 months, and informed consent. Patients with previous radiation in the head and neck area and recent oral cavity inflammation were excluded from the study. Twenty patients who met the inclusion criteria were enrolled onto group A.

Two pair-matched control patients for each patient case were assigned to group B, which consisted of 40 patients diagnosed with metastatic breast cancer and treated with intravenous ZA who did not develop ONJ. As previous studies suggested, development of ONJ is more probable with more infusions and longer treatment time.^7,10 Dose-matched controls (patients in group B) were randomly allocated from a total of 167 patients who fulfilled the inclusion and exclusion criteria. All group A patients received ZA treatment for 6 to 48 months. However, three patients received pamidronate before ZA treatment, and two patients received ibandronate after ZA treatment. These patients were individually matched with controls who similarly received pamidronate before or ibandronate after ZA treatment. Control patients received one less dose to three more doses (–1/+3 doses) than matched group A patients. Controls were also matched for age to remove any effect of ageing. Control patients were younger by 1 year or older by up to 3 years (–1/+3 years) than matched group A patients. Uniformity of socioeconomic status was assessed through social insurance type matching. In addition, all participants were recruited from Theagenio Hospital, which is the tertiary referral cancer hospital for Northern Greece.

To minimize selection bias, we included in the study all patients treated in the last 5 years. Differential misclassification and observer bias were not an issue as a result of the definite diagnosis, followed by treatment.⁹ The results of this study could be subject to recall bias, and this is further explained in the Discussion. Possible confounding factors were addressed via matching and regression modeling. A detailed interview based on a preformed questionnaire and revision of medical and dental records were performed for every patient in the study.

Development of ONJ in the patients with breast cancer receiving ZA treatment (group A or B) was set as the outcome (dependent variable). Independent dichotomous variables were routine dental care, history of tooth extraction, smoking habit, use of dentures, and root canal therapy during and 6 months after ZA treatment.

All variables were checked for normal distribution via Shapiro-Wilk test for normality. Should normality assumption be met, a two-tailed t test was used for between-group comparisons. Regarding age, a variable nonparametric Mann-Whitney U test was used because this variable did not meet the normality assumption in the control group. Pearson's ² test was used for social insurance matching.

Relative risks, approximated by crude and adjusted odds ratios (ORs) and corresponding 95% CIs, were estimated by univariate and conditional multivariate logistic regression, respectively. Both manual and automated fitting procedures were used. Automated model selection proved more parsimonious. Forward inclusion and backward elimination with likelihood ratio criteria were used. level was set at .05, whereas = .10 was used as the cutoff for variable removal in the automated model selection for multivariate logistic regression. Logistic regression models were determined to account for outcome better than would be expected by chance (P < .001 for both) via the Wald test and ² likelihood ratio test. Goodness of fit was examined by adjusted R². Tests for interactions were automatically commenced by the statistical package through the fitting procedure. All P values were derived from two-sided statistical tests.

Given the number of patient cases and the 2:1 control to patient case quotient, this study would detect a 6.4, 4.9, and 5.9 OR between patient cases and controls with 80% power at a 10%, 25%, and 50% control exposure rate, respectively.¹¹ Significance and logistic regression model calculations were made with the SPSS 15.0 package (SPSS Inc, Chicago, IL).

	RESULTS

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Regarding morbidity and disease-related costs attributed to ONJ, for the 20 patients in group A, we recorded a total of 234 visits (mean, 11.7 ± 7.1 visits; range, two to 28 visits) and 190 hospitalization days (mean, 15.8 ± 13.2 days; range, 3 to 52 days) at the maxillofacial department. These figures present an underestimation of the true morbidity because of the fact that some of these patients were also hospitalized in the oncology clinic before surgical procedures or for conservative treatment of ONJ.⁹ Social insurance status did not differ between patient cases and controls (Pearson's ², P = .801).

As expected, because of the age- and dose-matched design of the current study, mean age and dose number did not differ between the two groups (Table 1). Colinearity was assessed through a correlation matrix. As expected, age was found to be significantly correlated with use of dentures (Pearson's r = 0.489, P < .001). Relationship among independent variables was examined by the coefficient. Routine dental care significantly correlated with history of tooth extraction ( = 0.544, P < .001), root canal therapy ( = 0.307, P = .017), and use of dentures ( = 0.289, P = .025). Relationships between dental treatment and treatment procedures were logically expected. The strongest was recorded between dental care and history of tooth extraction.

Smoking, history of tooth extraction, root canal treatment, and use of dentures were inserted into multivariate logistic regression models after appraisal of univariate analysis results. Three multivariate models were used. In the first model, we backward eliminated the following four variables: smoking, history of tooth extraction, use of overdentures, and root canal treatment. The results are listed in Table 2. In the second model, only history of tooth extraction and use of overdentures were forward included. The second model yielded exactly the same OR, supporting the opinion that there was no critical overfitting in the first model. Routine dental care was excluded from these models because the values were high. However, in the third model, we forward included history of tooth extraction, use of overdentures, and routine dental care (Table 2). Importantly, use of dentures proved to be a significant risk factor for development of ONJ after adjusting for other variables in the three models (Table 2).

The present study does not have enough statistical power to exclude a possible association with smoking or even root canal therapy. Nonetheless, it includes 10 patients for each independent variable in the second multivariate logistic regression model¹² (Table 2).

	DISCUSSION

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ZA is the most potent BP,¹³ and the results presented in this article are unlikely to have been confounded by the use of other BP in five patient cases and 10 individually matched controls. Results from the current series suggest a link between ONJ and tooth extraction. More specifically, 10 of 20 patients who developed ONJ had recent tooth extraction compared with only three of 40 controls. In a recent report of three patients with ONJ, one patient had previous tooth extraction, and another had periodontal inflammation. The authors suggested that tooth extraction could be a risk factor for development of ONJ.³ Tooth extraction could be an indicator of poor oral hygiene, and therefore, we could have been measuring the confounder rather than the real independent risk factor. Nonetheless, oral hygiene is difficult to classify in a retrospective design. Another limitation concerns possible recall bias. However, because tooth extraction is publicly considered a bloody procedure, it is unlikely that controls would not remember having extracted a tooth recently or suspect a relationship between dental treatment and their breast disease during interview so as to deliberately deceive the interviewer. Detection bias could also have influenced our results because ONJ could be more easily picked up at a dental examination. However, the bothersome symptoms (halitosis, pain, swelling, fever, and odynophagia) of ONJ would be difficult to overlook. Actually, most, if not all, ONJ patients were referred to our department by their oncologist. Other types of bias were addressed via disease, sex, location, insurance type, age, and dose matching.

Tooth extractions and subsequent injury to the bone and oral mucosa expose usually germ-free tissues to the oral flora. When this occurs during BP treatment, it could predispose to ONJ as a result of reduced bone blood perfusion, reduced bone metabolism rates, increased osteoclast and osteoblast apoptosis, and defective mucosal barrier caused by increased keratinocyte apoptosis. BPs have been reported^6-10 to promote all of these pathophysiologic mechanisms.

Use of dentures was found to be a significant risk factor after adjustment for the other variables in this study. Therefore, our findings suggest that extra attention should be paid to patients receiving ZA treatment who have removable dentition. Bamias et al⁷ reported that two of their 17 ONJ patients had dentures. Use of dentures, especially if they are ill-fitting, might cause injury to the oral mucosa and dissolve the mechanical mucosal barrier, thus permitting entry of the oral flora into the bone.

Smoking does not seem to be an independent risk factor. However, smoking is a known risk factor for breast cancer,¹⁴ and the probability that it might be a confounding or effect-modifying factor cannot be diminished.

Root canal treatment seems to be a secure treatment option for patients receiving BP. However, regression modeling returned a debatable adjusted OR. Hence, further studies are needed to establish the safety of this treatment option in patients receiving BP.

Participants in this study who had visited their dentist during ZA treatment exhibited a trend towards less risk for development of ONJ. This result could be an effect of chance, or more likely, this study could have had insufficient power to detect an actual link. However, it is highly improbable that general dental care and subsequent maintenance of better oral hygiene would harm patients receiving ZA medication. Additionally, with patients receiving BP referred by oncologists, dentists would be aware of the risk of ONJ and, therefore, avoid tooth extractions.

Our study was not designed to assess the treatment duration effect because our controls were dose matched. It is probable that longer ZA treatment predisposes to ONJ.⁷ We preferred not to test treatment duration as an independent risk factor because our aim was to detect prognostic factors to avoid ONJ and not to propose reducing ZA doses as a preventive measure.

Existing literature suggests an etiopathogenetic link between BP and development of ONJ.^1,9,13 The mechanism is unlikely to be cancer-type specific, and thus, our results could also be generalized to patients receiving BP for other cancers or even for nonmalignant diseases. Some authors have suggested dental precaution measures¹⁵ even though, to date, no odds have been assigned to specific risk factors. To our knowledge, this is the first study addressing potential risk factors for development of ONJ. The case-control design is feasible and cost effective, but it cannot establish causality.

We are currently carrying out a prospective cohort study with breast cancer, prostate cancer, and multiple myeloma patients receiving BP treatment (ZA and ibandronate). In this study, the patients are closely observed, and many parameters are monitored. Results will be published when the study is concluded.

A retrospective chart review is underway at The University of Texas M. D. Anderson Cancer Center (Houston, TX) to obtain more information about the incidence, clinical features, and natural history of ONJ. More than 4,000 cancer patients being treated with IV BP who have complete dental records have been identified.¹³ At the time of writing, results from this study have not been published. NCT00127205 [ClinicalTrials.gov] (http://www.clinicaltrials.gov/ct2/show/NCT00127205) is a large, randomized, prospective, comparative, phase III, 3-year trial of IV BPs (ZA, clodronate, and ibandronate) as adjuvant therapy for primary breast cancer with a planned enrollment of approximately 6,000 patients that has had protocol modifications to include monitoring for ONJ.¹³

The outcome of the present study justifies referral by oncologists for baseline dental evaluation of every patient to be treated with IV BPs. Regular dental follow-up to avoid tooth extractions might play a protective role in the prevention of ONJ development. The results of the present study raise the current level of evidence linking dental-specific procedures with BP-induced ONJ from V to III.¹⁶ Further studies are needed to assess other potential risk factors and also to highlight the etiopathogenesis mechanism of ONJ.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Athanassios Kyrgidis, Stefanos Triaridis

Financial support: Athanassios Kyrgidis, Konstantinos Vahtsevanos

Administrative support: Athanassios Kyrgidis, Konstantinos Vahtsevanos

Provision of study materials or patients: Athanassios Kyrgidis, Konstantinos Vahtsevanos, Georgios Koloutsos, Charalampos Andreadis, Ioannis Boukovinas, Zisis Teleioudis

Collection and assembly of data: Athanassios Kyrgidis, Konstantinos Vahtsevanos, Georgios Koloutsos, Charalampos Andreadis

Data analysis and interpretation: Athanassios Kyrgidis, Konstantinos Vahtsevanos, Anna Patrikidou, Stefanos Triaridis

Manuscript writing: Athanassios Kyrgidis, Konstantinos Vahtsevanos, Charalampos Andreadis, Ioannis Boukovinas, Anna Patrikidou, Stefanos Triaridis

Final approval of manuscript: Athanassios Kyrgidis, Konstantinos Vahtsevanos, Charalampos Andreadis, Anna Patrikidou, Stefanos Triaridis

	ACKNOWLEDGMENTS

 
We thank Kitikidou Kyriaki, PhD, Lecturer of Statistics at Demokritos University of Thrace for her suggestions concerning the statistical analysis.

	NOTES

 
published online ahead of print at www.jco.org on June 23, 2008.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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3. Garcia Saenz JA, Lopez TS, Garcia PB, et al: Osteonecrosis of the jaw as an adverse bisphosphonate event: Three cases of bone metastatic prostate cancer patients treated with zoledronic acid. Med Oral Patol Oral Cir Bucal 12:E351–E356, 2007[Medline]

4. 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[Abstract/Free Full Text]

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8. Zervas K, Verrou E, Teleioudis Z, et al: Incidence, risk factors and management of osteonecrosis of the jaw in patients with multiple myeloma: A single-centre experience in 303 patients. Br J Haematol 134:620-623, 2006[CrossRef][Medline]

9. Magopoulos C, Karakinaris G, Telioudis Z, et al: Osteonecrosis of the jaws due to bisphosphonate use: A review of 60 cases and treatment proposals. Am J Otolaryngol 28:158-163, 2007[CrossRef][Medline]

10. Dimopoulos MA, Kastritis E, Anagnostopoulos A, et al: Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates: Evidence of increased risk after treatment with zoledronic acid. Haematologica 91:968-971, 2006[Abstract/Free Full Text]

11. Garcia-Closas M, Lubin JH: Power and sample size calculations in case-control studies of gene-environmental interactions: Comments on different approaches. Am J Epidemiol 149:689-693, 1999[Abstract/Free Full Text]

12. Concato J, Feinstein AR, Holford TR: The risk of determining risk with multivariable models. Ann Intern Med 118:201-210, 1993[Abstract/Free Full Text]

13. Ruggiero S, Gralow J, Marx RE, et al: Practical guidelines for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in patients with cancer. J Oncol Pract 2:7-14, 2006[Abstract/Free Full Text]

14. Baptista MZ, Altundag K, Akyurek S, et al: Tobacco smoking and breast cancer. Breast J 12:396-397, 2006[CrossRef][Medline]

15. Coleman RE: The role of bone markers in metastatic bone disease. Cancer Treat Rev 32:1-2, 2006 (suppl 1)[Medline]

16. American Society of Clinical Oncology: ASCO/NCCN quality measures: Breast and colorectal cancers, April 2007 update. http://www.asco.org/ASCO/Downloads/Cancer%20Policy%20and%20Clinical%20Affairs/NCCN/ASCO%20NCCN%20Quality%20Measures%20table%20web%20posting%20with%20CoC%200507.pdf

Submitted January 16, 2008; accepted April 24, 2008.

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