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J Dent Res. 2011 April; 90(4): 439–444.
PMCID: PMC3144129

Risk Factors for Osteonecrosis of the Jaws

a Case-Control Study from the CONDOR Dental PBRN
A. Barasch,1,* J. Cunha-Cruz,2 F.A. Curro,3 P. Hujoel,2 A.H. Sung,4 D. Vena,5 A.E. Voinea-Griffin,1 and the CONDOR Collaborative Group


Case reports and cohort studies have linked bisphosphonate therapy and osteonecrosis of the jaws (ONJ), but neither causality nor specific risks for lesion development have been clearly established. We conducted a 1:3 case-control study with three dental Practice-based Research Networks, using dentist questionnaires and patient interviews for collection of data on bisphosphonate therapy, demographics, co-morbidities, and dental and medical treatments. Multivariable logistic regression analyses tested associations between bisphosphonate use and other risk factors with ONJ. We enrolled 191 ONJ cases and 573 controls in 119 dental practices. Bisphosphonate use was strongly associated with ONJ (odds ratios [OR] 299.5 {95%CI 70.0-1282.7} for intravenous [IV] use and OR = 12.2 {4.3-35.0} for oral use). Risk markers included local suppuration (OR = 7.8 {1.8-34.1}), dental extraction (OR = 7.6 {2.4-24.7}), and radiation therapy (OR = 24.1 {4.9-118.4}). When cancer patients (n = 143) were excluded, bisphosphonate use (OR = 7.2 {2.1-24.7}), suppuration (OR = 11.9 {2.0-69.5}), and extractions (OR = 6.6 {1.6-26.6}) remained associated with ONJ. Higher risk of ONJ began within 2 years of bisphosphonate initiation and increased four-fold after 2 years. Both IV and oral bisphosphonate use were strongly associated with ONJ. Duration of treatment > 2 years; suppuration and dental extractions were independent risk factors for ONJ.

Keywords: osteonecrosis, jaws, bisphosphonates, risk factors


Osteonecrosis of the jaws (ONJ) is a rare clinical entity, which has historically been described in the context of severe local or systemic disease or after iatrogenic intervention (Almazrooa and Woo, 2009). Beginning in 2003, case reports, case-series, and cohort studies linked ONJ with bisphosphonate treatment, with prevalence varying from less than 1% to 28% (Wang et al., 2003; Ruggiero et al., 2004; Woo et al., 2006).

Bisphosphonates are indicated mainly for osteolytic conditions associated with cancer (Berenson et al., 1996, 2002; Hillner et al., 2003; Body, 2009) and osteoporosis (Devogelaer, 2000; Stafford et al., 2004), with efficacy in prevention of vertebral and hip fractures (Hortobagyi et al., 1996; Ross et al., 2003). Several bisphosphonates are available in the US, including alendronate, etidronate, ibandronate, pamidronate, risedronate, and zoledronic acid. Alendronate and risedronate alone accounted for > 3 million prescriptions in 2003, and this number has been steadily increasing, warranting rigorous study of potential side-effects (Stafford et al., 2004).

We conducted a case-control study in dental practices to determine the risk associated with bisphosphonates and to identify other risk factors for ONJ, including dental diseases and procedures. This article presents our main findings related to demographics, medical conditions, dental procedures, and systemic medications. Further information on specific dental diseases and procedures is presented elsewhere.


Study Design

We designed a protocol across the three National Institutes of Health-funded dental Practice-based Research Networks (PBRNs), headquartered in New York, NY (PEARL), Seattle, WA, and Portland, OR (Northwest PRECEDENT), and Birmingham, AL (DPBRN). General dentists and dental specialists from within and outside the network membership were informed about the study through mass mailings. Practitioners who had diagnosed ONJ cases and were interested in participating were asked to contact the respective network. Power analyses indicated that 170 ONJ cases would be necessary for detection of differences with a power of 80%. The joint protocol was approved by each PBRN’s Institutional Review Board.

Case Selection

The study population was drawn from dental practices within the geographic areas of the PBRNs. Inclusion criteria were age > 40 yrs old, no history of facial trauma or sickle cell disease, and diagnosis of ONJ with onset after January 1, 2003. ONJ was defined as maxillary or mandibular exposed bone of any size that clinically appeared necrotic, without regard to duration or cause. Since we included all osteonecrotic jaw lesions, we neither restricted cases to a minimum duration of 8 wks, nor excluded those with a history of radiation therapy (Khosla et al., 2007). Cases originated from primary, secondary, and tertiary care centers. Subsequent to identification of a case, practitioners were asked to contact the patient verbally and ask permission for contact by the researchers, who then obtained informed consent.

Control Selection

We enrolled three controls for each ONJ case, aiming to select them from the same primary care practice where a case was diagnosed. The inclusion criteria were age > 40 yrs old and no history of bone necrosis. For cases obtained from secondary or tertiary care centers, controls were selected from the general dental practice that referred the case or, if this was not possible, from a practice in the same geographic area. We performed no further matching.

Data Collection

Standardized dentist forms queried dental signs, symptoms, diagnoses, and procedures between 2000 and 2008 that preceded the diagnosis of ONJ by a maximum of 3 yrs. For example, for patients diagnosed with ONJ in 2007, the questionnaire covered the period 2004 to 2007. We recorded tooth loss, periodontal disease, caries, endodontic problems, gingival bleeding, suppuration, pain or sensitivity, neurosensory disturbances, and information on dental procedures and dates of their performance. For controls, we collected the same data beginning 3 yrs prior to interview date. ONJ-specific issues did not apply to controls. Dental records were accessed by the dentist or his/her designee, and data forms were completed and returned to the PBRN for analyses. For quality assurance, 10% of the records from each PBRN were re-abstracted by a research assistant and compared with the original.

Patients underwent a structured telephone interview conducted by trained research assistants at each PBRN, assessing ONJ characteristics (mouth location, date of onset, size, pain, duration, healing), oral hygiene, medical history (cancers, radiotherapy, bone diseases), occupational exposures (chemical industry, phosphorus exposure), demographics, education and lifestyle (race/ethnicity, alcohol and smoking history), and medications (oral and/or IV bisphosphonates, chemotherapy, antiretroviral medication, steroids, regular use of other drugs). ONJ-related questions did not apply to controls.


The primary exposure of interest was bisphosphonate therapy. Secondary exposures included therapeutic radiation to the jaws, diagnosis of cancer or osteoporosis, dental diagnoses and procedures, co-existing chronic diseases, and long-term use of systemic corticosteroids. These factors were selected based on their previous association with osteonecrosis. Duration, frequency, dose, and scheduling of each bisphosphonate and other details of exposure were collected during the patient interview. For cases, dental procedures occurring prior to ONJ development but within the same dental quadrant were labeled as “matched” procedures, while those in uninvolved quadrants were “unmatched”. Cases in which the location of ONJ was not known were excluded from the pertinent analyses. These data were dichotomized for controls as present or absent.

Statistical Considerations

Conditional logistic regression models were used to investigate the association between bisphosphonates and other factors with ONJ (SAS procedure LOGISTIC, SAS Institute, Cary, NC, USA). The case-control sets originating from dental practices were the stratification variables. Data from the three PBRNs were pooled, and OR and 95%CI were calculated. No adjustment for the network clustering was performed. Potentially confounding factors and multicollinearity were evaluated. Propensity score approaches (D’Agostino, 1998; Calvo-Alen et al., 2006) were used in a secondary analysis to control for strong associations between bisphosphonate exposure and the conditions for which bisphosphonates are prescribed. Covariates included general indicators of health, demographics, co-morbidities, dental diagnoses and procedures, and treatment with medications other than bisphosphonates.


We identified 308 cases of ONJ, of which 117 cases either refused participation or could not be contacted. Therefore, 191 cases together with 573 controls were included in the analyses (see Appendix). Bisphosphonate use was reported by 113 cases (83%) and 71 controls (15%), with a mean duration (standard error) of 5.6 (0.7) and 4.2 (0.6) yrs, respectively (Table 1). Duration and numbers and sizes of the ONJ lesions are depicted in Table 2.

Table 1.
Distribution (percent) of Participant Characteristics, Co-morbidities, Treatments, and Dental Procedures by Case/Control
Table 2.
Osteonecrosis of the Jaw Natural History Based on Participant Report

Bivariate Analyses

Compared with controls, more cases were aged > 60 yrs (OR 3.1 [95%CI 2.1-4.4]), had not finished high school (3.2 [1.6-6.7]), had income < $25,000 (2.7 [1.7-4.5]), and had a history of tobacco use (1.7 [1.2-2.3]). Patients with a history of any cancer had OR = 14.3 (95%CI 8.8-23.3) for ONJ compared with those without cancer. Similarly, patients who reported having osteoporosis (OR = 7.0 [95%CI 4.2-11.6]), diabetes (1.7 [1.1-2.8]), and anemia (3.1 [2.1-4.5]) had higher unadjusted associations with ONJ compared with individuals without these conditions.

Both oral (PO) and IV bisphosphonates were associated with ONJ (OR = 9.8 [95%CI 5.3-18.1] and 299.5 [70.0-1282.7], respectively), as were chemotherapy for cancer (25.7 [13.8-48.0]), radiation to the jaws (7.6 [4.3-13.6]), and use of systemic corticosteroids (2.2 [1.6-3.2]). For all cases, bisphosphonate use < 2, 2-5, and > 5 yrs had ORs (95%CI) of 13.9 (6.4-30.2), 32.3 (13.5-77.3), and 29.4 (12.7-68.3), respectively. When those with a history of cancer were excluded, the respective ORs became 5.2 (1.2-22.5), 11.4 (3.2-40.2), and 26.6 (5.3-133.6). Other bivariate analyses for these non-cancer patients (47 cases, 138 controls) revealed risk associations similar to those of the whole sample (data not shown).

Multivariate Analyses

In a model including demographics, dental risk factors, treatments and co-morbidities (all participants), oral suppuration (7.8 [95%CI: 1.8-34.1]), matched dental extractions (7.6 [2.4-24.7]), and therapeutic radiation for head and neck cancer (24.1 [4.9-118.4]) were associated with ONJ (Table 3). Use of oral bisphosphonates was a potent risk factor (OR = 12.2 [95%CI 4.3-35.0]). The OR for IV bisphosphonates did not converge due to rare use of this treatment in controls (95%CI 91.0- >999.9). Anemia was the only chronic medical condition with independent association (OR = 5.2 [95%CI 1.7-15.8]). The final model in Table 3 shows that duration of bisphosphonate use < 2 yrs was associated with a ten-fold risk of ONJ, while with duration > 2 yrs, that risk nearly quadrupled. Table 4 shows that among patients without cancer, bisphosphonate use (OR 7.2 [95%CI 2.1-24.7]), suppuration (11.9 [2.0-69.5]), and dental extraction (6.6 [1.6-26.6]) remained independently associated with ONJ.

Table 3.
Multivariate Model Results for All Participants
Table 4.
Multivariate Model Results for Participants without Cancer (Case = 30, Control = 81)

In the secondary analysis using propensity scores, bisphosphonate use remained associated with ONJ in all (OR = 11.8 [95%CI 5.9-23.6]) and in non-cancer patients (8.0 [2.3-28.2]).


Despite numerous publications, risk factors for ONJ, including bisphosphonate treatment, have not been clearly established. While association of ONJ with bisphosphonate use and dental extractions appeared relatively assured (Almazrooa and Woo, 2009), the strength of these associations remained poorly quantified. Evidence for other risk factors was mixed and weak. This case-control study, conducted in a broad cross-section of dental practices, confirms an elevated risk for ONJ among patients treated with bisphosphonates, with a large effect in the range suggestive of a causal link. All formulations of bisphosphonates (except etidronate, used by three participants only) were associated with ONJ.

Analyses by bisphosphonate agent also confirmed the expected differences by drug potency. The OR for IV zoledronic acid (100,000 times more potent than etidronate) and pamidronate were sizably larger than those for weaker oral formulations (alendronate). The significant association of less potent bisphosphonates with ONJ confirms previous reports (Bamias et al., 2005; Marx et al., 2005; Badros et al., 2006), and has significant clinical implications, since millions of patients have been treated with these drugs (Stafford et al., 2004; Silverman and Maricic, 2007). Our study was not designed to estimate prevalence or incidence; however, while the associations we report are large, the evidence suggests that absolute risks are possibly modest (Silverman and Maricic, 2007).

ONJ has also been associated with duration of bisphosphonate treatment (Woo et al., 2006). The minimum duration of use subsequent to ONJ development was reported to be 6 mos (Bamias et al., 2005; Marx et al., 2005; Badros et al., 2006). The mean duration of bisphosphonate treatments for ONJ diagnosis in these studies ranged from 1.6-4.7 yrs, depending on bisphosphonate type. Our results confirm that risk begins within 2 yrs of treatment, for both cancer and non-cancer patients, showing that even the less potent bisphosphonates are linked to ONJ after a relatively brief treatment period. The ORs for non-cancer patients (the vast majority of whom were taking oral bisphosphonates) increased substantially after 5 yrs, supporting the suggestion that a drug ‘vacation’ after 5 yrs of treatment may be reasonable (Black et al., 2006).

ONJ can occur in the setting of other diseases (Enwonwu et al., 2000; Robin et al., 2005; Sun et al., 2006) or due to iatrogenic factors (Schwartz and Kvorning, 1982; Tarassoff and Csermak, 2003; Najm et al., 2004; Talamo et al., 2005). We did find that ONJ was associated with several risk factors; however, many of these are indications for bisphosphonates, such as various cancers and osteoporosis. Associations with other systemic diseases like diabetes mellitus (Khamaisi et al., 2007) and anemia require further study. In the current study, only the latter remained an independent risk factor in models including bisphosphonate duration.

Pharmacological agents that have been associated with osteonecrosis at sites other than the jaws include corticosteroids (Almazrooa and Woo, 2009), cytotoxic drugs (Talamo et al., 2005), and multimodal antiretroviral therapies (Reddy et al., 2005). Our results showed that both corticosteroids and cytotoxic drugs were associated with ONJ in bivariate analysis, but after inclusion of dental factors and bisphosphonate use, there were no independent associations. We had too few patients on antiretroviral therapies to examine this association.

Prior to 2003, the most common risk factors for ONJ were ionizing radiation, ingested radioactive elements, and phosphorus (Woo et al., 2006). Data on the incidence of radiation-induced ONJ range from 0.4 to 56% of patients exposed to cancer-curative doses (Jereczek-Fossa and Orecchia, 2002). Our study included 46 cases and 26 controls with a history of radiation therapy to the head and neck, and this history demonstrated an independent association with a large effect size, confirming previous reports of radiation-induced osteonecrosis (osteoradionecrosis).

Our study has both strengths and limitations. Other studies found the prevalence of ONJ in cohorts of patients treated with IV bisphosphonate to be from < 1% to 28% (Badros et al., 2006; Boonyapakorn et al., 2008), depending on the population. Typically, the lower estimates included osteoporosis patients, while the higher figures were obtained in groups of cancer patients. Due to its case-control design, our study cannot contribute to this critical issue.

A second limitation is the fact that information about medication use was obtained from telephone interviews. Though patients were asked in a pre-interview mailing to help the process by listing all their past and current drugs prior to the call, this method is still subject to recall bias. Because bisphosphonates are taken once weekly or once monthly and require specific instructions after administration, it is possible that recall bias may be lessened. Another potential limitation is the three-center design, with data merged for final analysis.

A strength of our study is its conduct in community-based dental practices spanning the US rather than at academic medical centers, increasing the likelihood that our participants were more typical of the general population and strengthening generalizability. Several additional analyses tested the robustness of our findings, including the use of propensity scores to adjust for confounding by indication, supporting our main results.

In conclusion, this case-control study supports a causal link between bisphosphonates and ONJ. The highest risk was found for patients receiving more potent bisphosphonates, but substantial associations existed for oral-bisphosphonate-treated, non-cancer patients as well.

Supplementary Material


We wish to acknowledge the significant contributions of Jonathan Ship, who passed away during this study. A special acknowledgement goes to Dr. Ananda Desaranayake for his contribution to the development of this project. This study was supported by grants U01DE016747, U01DE016755, U01DE016750, U01DE016746, U01DE016754, and U01DE016752 from the National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA. Data from this manuscript were presented at the Annual Meeting of the American Association for Dental Research in Washington, DC, on March 4, 2010.


A supplemental appendix to this article is published electronically only at


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