Onset Of Osteonecrosis Of The Jaw Research Articles

Medication-Related Osteonecrosis of the Jaw, a Hidden Enemy. An Integrative Review

Background: Drug-induced osteonecrosis of the jaw (ONJ) ​​is a serious complication associated with prolonged use of antiresorptive (e.g., bisphosphonates and denosumab) and antiangiogenic drugs (e.g., bevacizumab and sunitinib) in patients with osteoporosis or cancer. With this situation, a progressive infection of the maxillary or mandibular bone and later an avascular necrosis of the bone occurs. The incidence of ONJ is higher in people with cancer who are frequently received high doses of antiresorptive drugs intravenously. Risk factors associated with antiresorptive or antiangiogenic therapy have been identified to possibly contributing to the onset of ONJ. Purpose: To review and analyze the current available therapeutic options to treat at-risk patients or who already have ONJ. Methods: In this integrative review of the literature, publications were searched in the ScienceDirect, PubMed, SciELO, and ResearchGate databases between 2003 and 2020. The search terms were “bisphosphonate-associated maxillary osteonecrosis,” “maxillary osteonecrosis associated with medication,” and “maxillary osteonecrosis.” Results: 64 articles were selected in which extractions are identified as the main risk factor for developing ONJ (52 % to 61 %). A second factor identified was the spontaneous appearance of bone necrosis lesions. Conclusions: It is important to implement preventive measures in medical and dental care before, during, and after antiresorptive and antiangiogenic treatments to minimize the risks of ONJ in patients.

Occlusal Trauma and Bisphosphonate-Related Osteonecrosis of the Jaw in Mice.

Osteonecrosis of the jaw (ONJ) is a serious adverse event that is associated with antiresorptive agents, and it manifests as bone exposure in the maxillofacial region. Previous clinical reports suggest that mechanical trauma would trigger ONJ in a manner that is similar to tooth extractions. To the best of our knowledge, there have been few detailed pathophysiological investigations of the mechanisms by which occlusal/mechanical trauma influences ONJ. Here, we developed a novel mouse model that exhibits ONJ following experimental hyperocclusion and nitrogen-containing bisphosphonate (N-BP) treatment. This in vivo model exhibited ONJ in alveolar bone, particularly in the mandible. Moreover, the experimental hyperocclusion induced remarkable alveolar bone resorption in both mouse mandible and maxilla, whereas N-BP treatment completely prevented alveolar bone resorption. In this study, we also modeled trauma by exposing clumps of mesenchymal stem cells (MSCs)/extracellular matrix complex to hydrostatic pressure in combination with N-BP. Hydrostatic pressure loading induced lactate dehydrogenase (LDH) release by calcified cell clumps that were differentiated from MSCs; this LDH release was enhanced by N-BP priming. These in vivo and in vitro models may contribute further insights into the effect of excessive mechanical loading on ONJ onset in patients with occlusal trauma.

Osteonecrosis of the jaw (ONJ) in radium 223 (Ra223)-treated metastatic castration-resistant prostate cancer (mCRPC) patients (pts) with exposure to zoledronic acid and/or denosumab.

5575 Background: Bone health agents (BHA) including denosumab, a monoclonal antibody, and Zoledronic acid (ZA), a bisphosphonate, are recommended for men with CRPC and bone metastases to prevent skeletal-related complications. ONJ occurs in about 5% of patients (pts) on BHA. The incidence of ONJ in pts treated with Ra223 and BHA remains unknown, particularly in those who receive sequential treatment of BHAs. Here we describe the rate of ONJ in a real-world setting in mCRPC pts treated with Ra223 in 3 groups: 1) denosumab alone, 2) ZA alone, and 3) sequential ZA /denosumab or vice versa. Methods: A retrospective analysis of a cohort of mCRPC pts with bone metastases who received Ra223. Follow-up was until date of death or last data entry. Chart inclusion criteria included patients who received Ra223 between November 2010 to August 2018 with documentations of data points. Results: A total of 177 pts received Ra223 between 11/2010 and 8/2018. Median age 73 at 1st Ra223 (range 40-93); Median PSA 15.8- at 1st Ra223 (range 0.1-1952); Demographics-AA-10, C-130, Asian-9, unspecified-28; Median Alk Phos 95 at 1st Ra233 (range 25-1515). 93 % (164/177) received BHA. Of the 164 who received BHA, 45% (73/164) received denosumab only, 37% (61/164) received ZA only, and 18% (30/164) received sequential treatment. ONJ developed in 9.7% (16/164) of all patients on BHA. Denosumab alone caused ONJ in 7 of 73 pts (9.6%). ZA alone caused ONJ in 6 of 61 pts (9.8%). ONJ occurred in 3 of 30 pts (10%) in the sequential group. The median number of doses of BHA before development of ONJ was 10 with denosumab, 20 with ZA, and 19.5 (denosumab) and 22 (ZA) in the sequential group. Conclusions: In patients treated with Ra223 and a BHA, the rate of ONJ is 9.7%. The rate of ONJ was similar in groups treated with denosumab alone, ZA alone, and sequential treatment of ZA and denosumab However, ONJ developed more quickly in patients on denosumab. We conclude that the risk of ONJ is increased in patients treated with Ra223 and BHA. ZA or sequential therapy appears to delay time to onset of ONJ compared to denosumab. Clinicians should be mindful of the toxic synergy between Ra223 and BHA. ZA may be the preferred BHA partner with Ra223.

Factors associated with osteonecrosis of the jaw in women with breast cancer receiving high-dose bisphosphonates to prevent breast cancer metastases as part of the SWOG 0307 trial.

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 of the jaw related to non-antiresorptive medications: a systematic review.

The reporting of osteonecrosis of the jaw (ONJ) related to anticancer agents without known antiresorptive properties (non-antiresorptives), such as antiangiogenics, tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, immune checkpoint inhibitors, and cytotoxic chemotherapy is increasing. To review characteristics of ONJ in cancer patients receiving non-antiresorptives. A systematic review of the literature between 2009 and 2017 was conducted by the Bone Study Group of MASCC/ISOO. Of 6249 articles reviewed and from personal communication, 42 ONJ cases related to non-antiresorptives were identified. No gender predilection was noted. Median age was 60years and ONJ stage 2 was most common, with predilection for posterior mandible. Exposed bone, pain, and infection were common at diagnosis. In comparison to bone targeting agents (BTAs), radiology, histology, and management were similar, with medication often discontinued. Delayed diagnosis (median 8weeks) was noted. Important differences included earlier time to ONJ onset (median 20weeks), absence of trigger event (40%), and greater likelihood of healing and shorter healing time (median 8weeks) as compared to BTA-related ONJ. Gastrointestinal cancers predominated, followed by renal cell carcinomas compared to breast, followed by prostate cancers in BTA-related ONJ, reflecting different medications. Data about non-antiresorptive-related ONJ is sparse. This type of ONJ may have better prognosis compared to the BTA-related ONJ, suggested by greater likelihood of healing and shorter healing time. However, the delay in diagnosis highlights the need for more education. This is the first attempt to characterize ONJ associated with different non-antiresorptives, including BRAF and immune checkpoint inhibitors.

Altered microRNA expression profile in the peripheral lymphoid compartment of multiple myeloma patients with bisphosphonate-induced osteonecrosis of the jaw.

Bisphosphonates are formidable inhibitors of osteoclast-mediated bone resorption employed for therapy of multiple myeloma (MM) subjects with osteolytic lesions. Osteonecrosis of the jaw (ONJ) is an uncommon drug-induced adverse event of these agents. MicroRNAs (miRNAs) are a group of small, noncoding RNAs nucleotides, which are essential post-transcriptional controllers of gene expression. They have a central role in the normal bone development. The goal of our study was to investigate 18 miRNAs, whose targets were previously validated and described in MM subjects without ONJ, in peripheral lymphocytes of MM subjects with bisphosphonate-induced ONJ. Utilizing reverse transcription quantitative polymerase chain reaction, we evaluated miRNAs in five healthy subjects and in five MM patients with ONJ. Our experimental data revealed that a diverse miRNA signature for ONJ subjects emerged with respect to control subjects. Using the filter for in silico analysis, among the 18 miRNAs, we recognized 14 dysregulated miRNAs. All these miRNAs were significantly over-expressed in patients vs controls (MIR-16-1, MIR-21, MIR-23A, MIR-28, MIR-101-1, MIR-124-1, MIR-129, MIR-139, MIR-145, MIR-149, MIR-202, MIR-221, MIR-424, MIR-520). Among them, six were strongly upregulated (fourfold upregulated and more). These miRNAs target numerous pathways and genes implicated in calcium ion binding, bone resorption, mineralization of bone matrix, and differentiation and maintenance of bone tissue. A modified microRNA expression profile after zoledronate therapy could participate to the onset of ONJ. Targeting these miRNAs could provide a new opportunity for the prevention or treatment of ONJ.

Duration of treatment with bisphosphonates at the time of osteonecrosis of the jaw onset in patients with rheumatoid arthritis. Review

IntroductionRheumatoid arthritis (RA) is a frequent and co-morbid condition. One of the main complications is induced osteoporosis. Treatments related to this complication significantly modify oral and implant management. Affected patients represent a population at intermediate risk of osteonecrosis of the jaw (ONJ). The objective was to search the literature for durations of treatment with bisphosphonates at the time of ONJ occurrence in patients with RA in order to obtain an average duration. Materials and methodsA bibliographic search in the PubMed/Medline database was carried out using the following equation “(osteonecrosis and jaw) and rheumatoid arthritis” with no time limitation. The primary study endpoint was the duration of treatment with bisphosphonates (BP) at the time of ONJ onset in patients with RA. ResultsTwelve articles accounting for 50 patients were included. Patients had had a median of 46.8 months of treatment with BP before ONJ occurred. Mean, minimum and maximum treatment times were 48.68, 6 and 120 months, respectively. The standard deviation was 27.77 months. DiscussionThe median treatment duration in our cohort of patients with RA was less than that reported for osteoporosis. We therefore, recommend that practitioners take additional precautions regarding oral surgery or implant procedures, particularly in patients with RA who have been treated with BP for more than 4 years.

A multicenter case registry study on medication-related osteonecrosis of the jaw in patients with advanced cancer

PurposeThis observational case registry study was designed to describe the natural history of cancer patients with medication-related osteonecrosis of the jaw (ONJ) and evaluate the ONJ resolution rate.MethodsAdults with a diagnosis of cancer and with a new diagnosis of ONJ were enrolled and evaluated by a dental specialist at baseline and every 3 months for 2 years and then every 6 months for 3 years until death, consent withdrawal, or loss to follow-up. The primary endpoint was the rate and time course of ONJ resolution. Secondary endpoints included frequency of incident ONJ risk factors, ONJ treatment patterns, and treatment patterns of antiresorptive agents for subsequent ONJ.ResultsOverall, 327 patients were enrolled; 207 (63%) were continuing on study at data cutoff. Up to 69% of evaluable patients with ONJ had resolution or improvement during the study. ONJ resolution (AAOMS ONJ staging criteria) was observed in 114 patients (35%); median (interquartile range) time from ONJ onset to resolution was 7.3 (4.5–11.4) months. Most patients (97%) had received antiresorptive medication before ONJ development, 9 patients (3%) had not; 68% had received zoledronic acid, 38% had received denosumab, and 10% had received pamidronate (56% had received bisphosphonates only, 18% had received denosumab only, and 21% had exposure to both).ConclusionsThese results are consistent with those observed in clinical trials evaluating skeletal-related events in patients with advanced malignancy involving bone. Longer follow-up will provide further information on ONJ recurrence and resolution rates between medically and surgically managed patients.

Osteonecrosis of the jaw in patients treated with denosumab for metastatic tumors to the bone: A series of thirteen patients.

This case series describes the course of osteonecrosis of the jaw (ONJ) in thirteen patients with metastatic bone tumors treated solely with denosumab. Patients on denosumab may be more prone to developing ONJ even without a risk/precipitating factor and they may develop ONJ early in their denosumab therapy. The outcomes of ONJ in ten patients following a period of denosumab discontinuation after the onset of ONJ were: 3 had complete resolution of symptoms, 4 patients' ONJ progressed, 2 patients' ONJ was unchanged and in 1 patient there was partial ONJ resolution. The role of drug discontinuation prior to an invasive dental procedure or after the onset of ONJ still remains debatable.

Osteonecrosis of the jaw from bone anti‐resorptives: impact of skeletal site‐dependent mesenchymal stem cells

Recently, two Letters to the Editor addressed the use of bone mesenchymal (Gonzalvez-Garcia et al., 2012) and hematopoietic (Elad et al., 2012) stem cells in the management of osteonecrosis of the jaw (ONJ), a common complication of bone anti-resorptive therapies. Clearly, bisphosphonates and denosumab are highly efficacious in controlling dysregulated bone remodeling in osteoporosis, Paget’s disease, multiple myeloma and skeletal events of cancer metastasis, however ONJ is still an unpredictable recalcitrant oral complication (Fusco et al., 2011, Stopeck et al., 2010). The underlying pathophysiological mechanism of ONJ is still unclear, so prevention of ONJ is challenging. Also, there is paucity of randomized controlled clinical trials on ONJ therapies, so management algorithms are still empirical (Moretti et al., 2011, Stockmann et al., 2010, Montebugnoli et al., 2007). Both bisphosphonates and denosumab directly inhibit osteoclasts, but bisphosphonates also indirectly inhibit osteoclastic activity through osteoblasts and bone mesenchymal stem cells (BMSCs) both of which express the cell surface ‘receptor activator of NFκB ligand’ (RANKL) known to interact with RANK on osteoclast precursors (Nishida et al., 2005, Roelofs et al., 2006). Since BMSCs can differentiate into multiple cell types including pre-osteoblasts and osteoblasts, some investigators have successfully transplanted BMSCs to treat ONJ both clinically and in animal studies (Cella et al., 2011, Kikuiri et al., 2010, Li et al., 2013). The function of BMSCs in these studies, though attributed to immune modulation does not explain the jaw-specific character of ONJ. ONJ, induced by bone anti-resorptives specifically targets the jaw unlike other forms of osteonecrosis in response to irradiation (osteoradionecrosis), infection (osteomyelitis), corticosteroid therapy (steroid-induced osteonecrosis) and alcoholism (alcohol-induced osteonecrosis) that can develop in non-oral skeletal sites (Akintoye & Hersh, 2012). It is still unclear why ONJ targets orofacial bones, so the successful use of BMSC transplants to treat ONJ draws attention to possible roles of jaw-specific characteristics of orofacial BMSCs (OFMSCs) in ONJ pathogenesis and its preference for oral bone. It has been shown that BMSCs are phenotypically and functionally site-specific in terms of their survival, differentiation and response to growth factors when compared to MSCs from axial/appendicular bones (Akintoye et al., 2006, Aghaloo et al., 2010). Moreover, OFMSCs are more responsive to bisphosphonate and irradiation relative to non-oral BMSCs (Damek-Poprawa et al., 2010, Stefanik et al., 2008). These jaw specific characteristics of OFMSCs could shed some light into the preferential jaw localization of ONJ as well as high incidence of jaw osteoradionecrosis following head and neck cancer radiotherapy (Damek-Poprawa et al., 2010, Stefanik et al., 2008). Osteogenic differentiation and osteoclast recruiting abilities of BMSCs are necessary for bone homeostasis and repair; therefore, it is possible that anti-resorptives such as bisphosphonate and denosumab apparently uncouple osteoblast-osteoclast balance in a skeletal site-specific pattern to favor onset of ONJ. The elusiveness of mechanisms that underlie jaw-specific nature of ONJ has made prevention and complete cure of ONJ challenging without invasive surgery. Further understanding of OFMSCs functions and cellular interactions in ONJ could shed more light on its pathogenesis and promote development of potential preventive therapies.

Incidence of osteonecrosis of the jaw in patients receiving denosumab or zoledronic acid for bone metastases from solid tumors or multiple myeloma: Results from three phase III trials.

9640 Background: In patients with metastatic bone disease (MBD), the use of antiresorptive therapies such as denosumab or zoledronic acid (ZA) reduces the risk of skeletal-related events but is associated with a small risk of osteonecrosis of the jaw (ONJ). Two phase 3 clinical trials of denosumab vs ZA in patients with MBD showed overall cumulative ONJ incidences to be 3.8% to 4.7% at approximately 5 years of treatment with denosumab across blinded and open-label extension phases. ONJ associated with ZA was only assessed in the blinded treatment phases, as patients switched to denosumab once superior efficacy was demonstrated. Here we report incidence rates of ONJ by first vs subsequent years of exposure for the blinded treatment phase of all three phase III clinical trials. Methods: Patients (n = 5,677) with bone metastases from solid tumors or multiple myeloma received either SC denosumab 120 mg and IV placebo or IV ZA 4 mg (adjusted for renal function) and SC placebo Q4W in the double-blinded treatment phase of each trial. Patients who received ≥ 1 active dose during the blinded treatment phase were included in this analysis for up to 44.5 months of denosumab exposure and 41.3 months of ZA exposure. Oral assessments were conducted at baseline and every 6 months thereafter by the investigator or other qualified examiner. Potential ONJ events were independently adjudicated by a blinded committee of experts. Results: The median (Q1, Q3) time to onset of ONJ was similar in both treatment groups (15.6 [9.5, 20.0] months for denosumab, 15.8 [11.0, 23.6] months for ZA). Cumulative incidence rates of ONJ during the blinded treatment phases for all three trials by patient-years of follow-up are shown below (Table). Conclusions: The incidence of ONJ increased with longer duration of antiresorptive exposure. There were no significant differences between treatment groups in ONJ incidence at year 1 or beyond. Clinical trial information: NCT00321464; NCT00330759; NCT00321620. [Table: see text]

Osteonecrosis of the Jaw Onset Times Are Based on the Route of Bisphosphonate Therapy

Osteonecrosis of the jaw (ONJ) has been reported to be associated with patients receiving bisphosphonate (BP) therapy. There are many reports that suggest that the time of exposure to BPs is a significant risk factor for ONJ and that the greatest risk occurs after dentoalveolar surgery. The aim of this study was to retrospectively investigate the duration of BP therapy and related events before the onset of ONJ based on an intravenous (IV) or oral route of administration. We conducted a retrospective cohort study of patients referred to our institution to identify the onset of ONJ based on the exposure to BP therapy and associated triggers (ie, dentoalveolar surgery or spontaneous occurrence) based on the route of BP administration. Demographic data (ie, age, gender, and race), medical diagnosis related to BP therapy, and information as to whether the BP therapy was continued at the time of ONJ diagnosis were also collected. We reviewed the records for 114 patients with a history of ONJ. We divided patient cohorts by route of BP administration, with 76 patients having a history of IV BP therapy and 38 patients having a history of oral BP therapy. The overall onset of ONJ was earlier in the IV BP group (median, 3 years) compared with the oral BP group (median, 5 years). There was no statistical difference in the duration to occurrence of ONJ associated with dental extraction compared with spontaneous occurrence for both the IV and oral BP groups. The median onset of ONJ for patients undergoing IV BP therapy occurs earlier than the median onset for patients undergoing oral BP therapy, and there was no difference in onset occurring spontaneously and after dental extraction. The significance of these findings suggests that patients who receive IV BP therapy should be closely evaluated after the initiation of BP therapy. The lack of evidence suggesting greater onset after dental extraction may provide clinical support for dentoalveolar surgery that is indicated for patients with a history of BP therapy. Research focusing on the clinical circumstances and physiologic events during early antiresorptive therapy may provide insight as to the critical risk factors.

Osteonecrosis of the jaw (ONJ) in patients with renal cancer treated with bisphosphonates (BPs) and sunitinib or other targeted therapy (TT) agents: A multicenter survey.

e15182 Background: ONJ has been very rarely reported in patients (pts) suffering from bone metastases of renal cell cancer (RCC) treated with BPs, such as pamidronate (P) and zoledronic acid (Z). Recently reports of ONJ cases among cancer pts receiving TT agents (sunitinib, bevacizumab, sorafenib, etc) w/o BPs have been published, including few cases among RCC pts. TT agents have been consequently suspected to be a possible risk factor for ONJ. On December 2010, EMA (European Medicine Agency) issued two safety warnings about ONJ risk after sunitinib or bevacizumab treatment; in the “dear doctor” alert letters, manufacturers reported the following data about ONJ cases registered among patients treated on clinical trials or on post-marketing setting (in all types of cancer): 27 ONJ cases among 101.400 pts after sunitinib and 55 ONJ cases among 800.00 pts after bevacizumab worldwide. Methods: We conducted a limited survey, asking three Medical Oncology units and four referral Oral Medicine and Surgery centres (involved in ONJ tertiary care), in different regions of Italy, to look for ONJ and RCC in their database. Nineteen cases of ONJ in RCC pts have been found. Available details of oncologic and dental history have been collected so far of 16 pts; of further 3 cases data reporting authorization is ongoing. Results: Pts characteristics of 16 evaluated pts: sex: 13/3 M/F; median age 63 years (range 45-72). BP treatment: 13 Z, 1 P, 1 Z+P, 1 Ibandronate. BP treatment duration at the ONJ onset: 12 months (range 1-36). Latest TT treatment at the ONJ diagnosis time: sunitinib (13 cases), sorafenib (1), bevacizumab (1), deforolimus (1). Previous treatments: sorafenib (3), IL2, capecitabine. Site of ONJ: 9 in mandible, 4 in maxilla, 2 in both (1 unspecified). Possible risk factors or precipitating events, such as teeth extraction, oral surgery, dental implants, have been reported on 8/16 cases. Conclusions: Incidence of ONJ in RCC pts is largely underestimated in literature. In selected Italian centers, an unexpected rate of ONJ among RCC pts has been observed. We planned a new survey, enlarged to medical oncology units and oral care centers in all Italian regions.

PS1-31: Osteonecrosis of the Jaw in Two Dental PBRN Health Plans

Objectives: Osteonecrosis of the jaw (ONJ) has been recently associated with exposure to bisphosphonates (BPs). Incidence and risk factors are ill-defined. This Dental PBRN study (www.dpbrn.org; support: DE-16746, DE-16747) used electronic records from two participating health plans to estimate ONJ incidence and assess whether BP use increased the likelihood of ONJ. Methods: We used multiple search strategies and manual chart reviews to identify ONJ cases in members of Kaiser Permanente Northwest and HealthPartners of Minnesota. Our cohort was members age 35 and older with medical and pharmacy coverage for at least one year during 1994–2006. We used a keyword search of electronic physician notes to flag suspected cases among patients with a diagnosis or procedure indicative of ONJ and then confirmed cases through manual chart review. Oral surgeons and general dentists identified additional cases among cohort members. We used logistic regression to estimate the odds of ONJ from BP exposure, adjusting for other risks. Results: 37,290 of 572,602 cohort members had a diagnosis or procedure indicating the potential for ONJ. A key word search of physician notes and chart review found 14 ONJ cases; 5 more cases were found through dental providers. Six cases (31.6%) had an oral BP dispense prior to ONJ onset, compared to 21,163 cohort members (3.7%). Eight cases (42.1%) had a history of cancer, and 5 (26.3%) had osteoporosis, compared to 71,776 (12.5%) and 23,392 (4.1%), respectively, among all cohort members. Univariate and multivariate logistic regression were inconclusive due to the small number of confirmed ONJ cases. Conclusions: The incidence of ONJ in this cohort was very low and limited our ability to assess risks. When compared to the larger cohort, the higher frequencies of oral BPs, cancer, and osteoporosis among ONJ cases suggest these may be risk factors for ONJ. The low number of cases resulted in logistic regression outcome predictors that were no better than random. The rarity of ONJ cases in our study may be good news for the millions of adults currently taking oral bisphosphonates, although more data are needed before we know for sure.

Biphosphonates-related osteonecrosis of the jaw: Clinical and physiopathological considerations

Since osteonecrosis of the jaw was related to biphosphonate administration by Marx, studies showing clinical symptoms, drug and surgical therapies overwhelmed the literature. Furthermore, the literature demonstrated the correlation between chronic biphosphonate adsumption and osteonecrosis of the jaw onset. Nitrogen-containing biphosphonates are widely used for the management of metastatic cancer, for prevention and treatment of osteoporosis, for the treatment of Paget's disease, and for the management of acute hypercalcemia. According to our experience, the treatment of BRON-J's lesions is difficult and prolonged. For this reason, in order to avoid these complications it is mandatory to perform a risk staging in patients who must undergo biphosphonate administration. When pharmacologic treatments with antibiotics and local antiseptics are not able to control the development of BRON-J's complications, the clinicians should perform radical surgical treatments such as the resection of the bone involved.

Letter to the Editor: Re: "Implant Placement With or Without Simultaneous Tooth Extraction in Patients Taking Oral Bisphosphonates: Postoperative Healing, Early Follow-Up, and the Incidence of Complications in Two Private Practices".

To the Editor: Re: Implant Placement With or Without Simultaneous Tooth Extraction in Patients Taking Oral Bisphosphonates: Postoperative Healing, Early Follow-Up, and the Incidence of Complications in Two Private Practices. Fugazzotto PA, Lightfoot WS, Jaffin R, Kumar A. (J Periodontol 2007;78:1664-1669). Recently, Fugazzotto et al. reported the results of a study showing that a history of oral bisphosphonate use was not found to be a contributing factor to the development of osteonecrosis of the jaw (ONJ) following implant placement in edentulous ridges or tooth extraction with immediate implant placement.1 This conclusion was based on two practice-based patient populations including 61 patients. No osteonecrosis was noted immediately postoperatively or during the follow-up period that lasted an average of 3.3 years. We find the conclusion of this study challenging because we see two major discrepancies between the study design and the results. If left unnoticed or misinterpreted, these discrepancies might give the reader the wrong impression about the safety of implant placement in patients administered oral bisphosphonates. First, the mean duration period of oral bisphosphonates described in this study is too short relative to the information available in the literature2 about the average onset of ONJ in patients administered oral bisphosphonates. In a recent study2 describing a group of 11 patients diagnosed with oral bisphosphonate–related ONJ, the mean duration of alendronate use before developing ONJ was 4.1 years. In the present study, only 26 of the 61 subjects used oral bisphosphonates ≥4 years before implant placement. Moreover, only four of these subjects used 70 mg alendronate per week, which is the standard regimen for osteoporosis; the remaining 22 subjects used only 35 mg alendronate per week. Since the accumulating doses of bisphosphonates probably play a major role in the occurrence of ONJ, the risk for osteonecrosis in these 22 patients may be even lower than was reported in patients using the standard regimen. Second, according to the data provided by the manufacturer of the most prescribed oral bisphosphonate,∗ the estimated incidence of ONJ in their records is 0.7 cases per 100,000 person-years of exposure.3 Based on our patient population, we suspected that the estimated incidence in Israel may reach one case of osteonecrosis per 4,000 patients administered oral bisphosphonates.2 Since this article2 was submitted, at least six additional patients were diagnosed with oral bisphosphonate–related osteonecrosis at our clinics, which indicates an even higher incidence in Israel. Mavrokokki et al.4 reported the frequency of ONJ in osteoporotic patients, mainly on a weekly oral alendronate protocol, to be one in 2,260 to 8,470 patients. In this study based on Australian data, if extractions were carried out, their calculated frequency was one in 296 to 1,130 cases. Even if the incidence of ONJ after dento-alveolar surgery is as high as the Australian data, a study including 61 patients is too small to demonstrate the actual risk level for the development of osteonecrosis in patients taking oral bisphosphonates. As the authors wrote, a large-scale cohort study is the preferred study design to allow a conclusion about the contribution of oral bisphosphonates to the development of ONJ. We are aware of the fact that the current literature3 points to a relatively small risk for the development of oral bisphosphonate–related ONJ. However, similar to the approach of the American Dental Association Council on Scientific Affairs,3 we believe that the risks and benefits should be discussed with the patient early during the dental treatment plan. Although data from the Fugazzotto et al. study may be used as part of a meta-analysis in the future, their current conclusion cannot be used as a proof for the safety of dental implant placement in this patient population. After alternative dental treatment plans are presented to patients with their informed consent, the patients may decide to choose a treatment plan that includes the placement of dental implants. Nevertheless, until better data are available, the dentist should not ignore this risk.

Bisphosphonate-associated osteonecrosis of the jaw: a review of 35 cases and an evaluation of its frequency in multiple myeloma patients

Over a period of 28 months, we observed five cases of osteonecrosis of the jaw (ONJ) in cancer patients treated with bisphosphonates (BP) at our institution. This prompted us to undertake a retrospective, multicenter study to analyse the characteristics of patients who exhibited ONJ and to define the frequency of ONJ in multiple myeloma (MM). We identified 35 cases in Gruppo Italiano Studio Linfomi centers during the period 2002 – 05. The median time from cancer diagnosis to the clinical onset of ONJ was 70 months. In these 35 cases of ONJ, 24 appeared 20 – 60 months after starting BP treatment. The time for the onset of ONJ was significantly shorter for patients treated with zoledronic acid alone than for those treated with pamidronate followed by zoledronic acid. The frequency of ONJ in the MM group during the study period was 1.9%, although the nature of the present study may have resulted in an underestimation of ONJ cases. Our analysis strongly suggested an association between the use of BP and the occurrence of ONJ, although we were unable to identify any definite risk factors with a retrospective study. The most frequently ONJ-associated clinical characteristics were chemotherapy treatment, steroid treatment, advanced age, female sex, anemia, parodonthopaties/dental procedures and thalidomide (in the case of MM patients).