Risk Of Osteonecrosis Of The Jaw Research Articles

An Aromatase Polymorphism (g.132810C>T) Predicts Risk of Bisphosphonate-Related Osteonecrosis of the Jaw

Bisphosphonate (BP)-related osteonecrosis of the jaw (ONJ) is an unpredictable, debilitating adverse effect. Recently, genetic polymorphisms have arisen as promising tools to identify patients with a higher risk of drug-related adverse events. We aimed to examine the association between the aromatase polymorphism g.132810C>T, and the estrogen receptor polymorphisms g.156705T>C and g.156751A>G, and the risk of BP-related ONJ. Eighty-three subjects were included in the study. A clinical and radiological examination was conducted on oncologic subjects treated with zoledronic acid. Subjects with histologically confirmed ONJ were included in the test group (n = 30) whereas subjects with good oral health were included in control group (n = 53). Aromatase and estrogen receptor polymorphisms from blood samples were analyzed. The aromatase g.132810C>T polymorphism displayed an over-representation of the TT genotype in the test group (36.67 vs 16.98%; p < 0.05). There was no significant difference in either estrogen receptor polymorphism genotype frequency between the test and control groups. Our data suggest a role for the g.132810C>T polymorphism in predicting ONJ risk. These results can pave the way to the personalization of BP therapy, based on individual genotype.

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

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

Bone necrosis around dental implants: a patient treated with oral bisphosphonates, drug holiday and no risk according to serum CTX

Osteonecrosis of the jaw (ONJ) may appear following certain oral surgery procedures in patients treated with oral bisphosphonates (OB). Guidelines for the treatment of these patients were set out in the American Association of Oral and Maxillofacial Surgeons (AAOMS) Position Paper on Bisphosphonate-Related Osteonecrosis of The Jaws (Position Paper) and Approved by the Board of Trustees in September 2006. For the AAOMS the placement of implants in these patients is not contraindicated. In addition, the serum C-terminal telopeptide bone suppressor marker (CTX) test is available to determine the risk of ONJ. A case is presented of ONJ in a patient with 6 months of OB discontinuation (“drug holiday”) before dental implant placement (following the guidelines of the AAOMS) and with no risk of osteonecrosis according to the serum CTX value (340 pg/ml). The wound healed favorably with complete healing at 7 months. In this case, the serum CTX test must be questioned as to its predictive value of ONJ, and more reliable markers of this risk are needed. Key words:Bisphosphonates, dental implants, bone necrosis, serum CTX.

Children and adolescents treated with neridronate for osteogenesis imperfecta show no evidence of any osteonecrosis of the jaw

Over recent years, several reports have been published on unusual cases of osteonecrosis of the jaw (ONJ) in adults using second- and third-generation nitrogen-containing bisphosphonates such as pamidronate, alendronate, risedronate and zoledronate, but no case has ever been reported either in children or in adult patients taking neridronate. Children and adolescents affected by osteogenesis imperfecta (OI) could belong to a high-risk group for ONJ because bone fragility in OI is associated with a connective tissue malfunction. The purpose of this study is to evaluate the incidence of ONJ in a pediatric population treated with neridronate for OI. A total of 102 pediatric patients with OI who received neridronate infusions for a mean of 6.81 years (SD ± 3.06 years) were clinically assessed for possible ONJ. Eligibility criteria for participation included patients between 1.2 and 24 years old who received cyclical neridronate infusions for at least 1 year. All the patients were reviewed to determine duration, dosage and cumulative dose of their bisphosphonate therapy and were examined clinically to assess their oral health status. We have not demonstrated any occurrence of ONJ in our patients. In conclusion, at the moment insufficient data are available to prove a greater risk of ONJ in children with OI than in children affected by other forms of bone fragility. However, cases may emerge in future because the risk of ONJ seems to be related to the cumulative dose and the duration of therapy.

Zoledronic acid inhibits macrophage SOCS3 expression and enhances cytokine production.

Suppressor of cytokine signaling-3 (SOCS3) has multiple functions including inhibition of Janus kinase (Jak) activity, regulation of protein degradation, and suppression of cytokine signaling. SOCS3 modulates macrophage response to cytokines such as IL-6 and leptin that are systemically induced in obesity. Obesity is a suspected risk factor for SOCS3-related pathology such as rheumatoid arthritis and Crohn's disease as well as zoledronic acid (ZA)-induced osteonecrosis of the jaw (ONJ). Thus, understanding the ability of bisphosphonates to modulate SOCS3 is necessary to qualify their contribution to these disorders. ONJ occurs in up to 10% of patients using intravenous bisphosphonates and has an unknown pathogenesis that may be linked to decreased bone turnover, altered vascularity, bacterial invasion, and compromised wound healing. Given the increased risk of ONJ with obesity and importance of macrophages in wound healing, we hypothesized that amino-bisphosphonates could contribute to the pathogenesis of ONJ by regulating macrophage responses to cytokines such as leptin and IL-6. We report that ZA is a novel inhibitor of SOCS3 in primary macrophages and human ONJ biopsy specimens. Inhibition of SOCS3 by ZA resulted in significant increases in IL-6 production. SOCS3 transcription is regulated by nuclear accumulation of phosphorylated-Stat3 (P-Stat3). We found that ZA decreased phosphorylation of Stat3 in a mevalonate-pathway dependent manner. However, restoration of P-Stat3 was not sufficient to correct SOCS3 inhibition. We propose that disruption of macrophage SOCS3 expression by amino-bisphosphonates such as ZA may be a novel contributor to inflammatory phenotypes in obesity and the pathogenesis of ONJ.

Het plaatsen van implantaten bij patiënten die bisfosfonaten gebruiken

Dentists are with increasing frequency confronted with patients who are being treated with bisphosphonates for certain bone diseases, hypercalcaemia, and bone metastases of solid malignancies. A side effect of the use of bisphosphonates is osteonecrosis of the jaw. Bisphosphonate-induced osteonecrosis of the jaw occurs mainly after treatment with intravenous bisphosphonates and to a much lesser extent after oral administration of bisphosphonates. The question remains whether oral implants can be safely placed in patients using bisphosphonates. A survey of the literature shows that the risk ofosteonecrosis of the jaw and loss of oral implants is not increased when the implants are placed within 3 years after starting treatment with oral bisphosphonates. After this period there is the possibility of a slightly increased risk of complications. The possibility of complications is higher in patients receiving the intravenous bisphosphonates, and, therefore, elective surgical treatments is not advocated.

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.

Commentary: Role of Bone-Modifying Agents in Metastatic Breast Cancer

Commentary: Role of Bone-Modifying Agents in Metastatic Breast Cancer

Risk Factors for Osteonecrosis of the Jaws

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.

RANK ligand inhibition in bone metastatic cancer and risk of osteonecrosis of the jaw (ONJ): non bis in idem?

The purpose of this study was to assess the necessity of post-marketing safety monitoring focused on osteonecrosis of the jaw (ONJ) in patients with bone metastatic cancer treated with denosumab (AMG162). The ONJ safety data from three randomized phase III trials were pooled, and risk ratios and power were computed using traditional methods and simulation. A total of 89 ONJ cases (1.57%; 95% CI, 1.26-1.92) were reported with 52 (1.83%; 95% CI, 1.37-2.39) occurring in the denosumab group (n = 2,841) and 37 (1.30%; 95% CI, 0.92-1.79) in the zoledronic acid group (n = 2,836). Overall, the pooled risk ratio (RR) for ONJ was 1.40 (95% CI, 0.92-2.13; p = 0.11). In the trials reporting superior therapeutic efficacy of denosumab, the RR for ONJ was 1.61 (95% CI, 0.99-2.62; p = 0.052). However, neither separately nor pooled had any trial adequate power (>80%) to detect excess relative risks of ONJ of up to 76%, assuming fixed ONJ rates in the control arms. The joint power of the trials to detect the observed excess relative risk of 40% was only 36%. The rate of mucosal healing in patients with ONJ appeared similar in both groups (RR, 1.28; 95% CI, 0.66-2.45; p = 0.5). Although the overall frequency of ONJ was low, post-marketing risk-benefit studies with this novel compound appear warranted focusing specifically on this rare toxicity, which can potentially have a high impact on quality of life.

Biochemical markers of bone turnover in osteonecrosis of the jaw in patients with osteoporosis and advanced cancer involving the bone

Osteonecrosis of the jaw (ONJ) has been hypothesized to result in part from a relative "oversuppression" of normal physiologic bone remodeling at the jaw brought about by bisphosphonate therapy. Biochemical markers of bone turnover give readily measurable information on integrated systemic bone remodeling activity, as measured by blood and urine assays. The intra- and interassay variability of most currently available assays is less than 10%, although many biological factors can influence levels of bone turnover markers. Bone turnover markers may show a dynamic response to changes in clinical status for a given disease state. Elevated bone turnover on and off treatment appears to predict adverse clinical consequences in both osteoporosis and cancer. Bisphosphonates effectively decrease the level of the bone turnover markers with a pattern depending on the marker, the bisphosphonate, the dose regimen, and the disease. However, long-term (10-year) treatment with bisphosphonates for osteoporosis does not appear to result in a progressive decline in bone turnover, as measured by markers and bone histology. The effects of long-term (greater than 2 years) treatment with monthly intravenous bisphosphonates on bone turnover markers in cancer are unknown. Discontinuation of bisphosphonate therapy appears to allow a recovery of bone turnover, which is related to the bisphosphonate, the duration of therapy, and the disease being treated. At this time, data are limited with regard to the utility of bone turnover markers in assessing risk for ONJ and whether bone marker-directed bisphosphonate holidays would be useful in prevention or treatment of ONJ.

Long-term treatment with bisphosphonates and their safety in postmenopausal osteoporosis

Bisphosphonates are the leading drugs for the treatment of osteoporosis. In randomized controlled trials (RCTs), alendronate, risedronate, and zoledronate have shown to reduce the risk of vertebral, nonvertebral, and hip fractures, whereas RCTs with ibandronate show antifracture efficacy at vertebral sites. Bisphosphonates are generally well tolerated and safe. Nevertheless, adverse events have been noted, and it is important to consider the strength of the evidence for causal relationships. Effects on the gastrointestinal tract and kidney function are well recognized, as are transient acute-phase reactions. Atrial fibrillation was first identified as a potential adverse event in a zoledronate trial, but subsequent trials and analyses failed to substantiate an association with bisphosphonates. Case reports have suggested a relationship between oral bisphosphonates and esophageal cancer, but this has not been demonstrated in epidemiologic studies. A possible association between bisphosphonate use and osteonecrosis of the jaw (ONJ) has also been suggested. However, the risk of ONJ in patients with osteoporosis appears to be very low, with no evidence from prospective RCTs of a causal association. There are reports of occasional occurrence of subtrochanteric or diaphyseal fractures in osteoporotic patients, but an association with bisphosphonate therapy is not substantiated by epidemiologic studies or prospective RCTs.

Osteonecrosis of the jaw induced by clodronate, an alkylbiphosphonate: case report and literature review

To report on a case of osteonecrosis of the jaw (ONJ) in a patient treated with clodronate, an alkylbiphosphonate, and to draw attention to the risk of ONJ following treatment with all biphosphonates, whether they are alkyl- or amino-biphosphonates. Beginning at age 58 years, a female patient took clodronate for almost 13 years for a metastatic bone cancer. She also underwent chemotherapy and radiotherapy. Three months after the end of biphosphonate therapy, she suffered from toothache, and tooth 27 (left maxillary second molar) was extracted. A maxillary focus of osteitis with an oral sinus communication was discovered, and a maxillofacial denture prosthesis was grafted in September 2006. Some days later, the patient consulted her dentist for an ulceration of the oral cavity floor in front of tooth 33 (left mandibular canine) extending to the left inferior side of the lip. In October 2006, teeth 33 and 34 (left mandibular first premolar) were extracted. No secondary infection occurred. A complete healing was only observed 3 months after the last extraction. ONJ due to alkylbiphosphonate treatment was diagnosed as bone reconstruction and mucous cicatrisation were delayed. A systematic review was carried out to identify all cases of alkylbiphosphonate-induced ONJ by searching the Medline and Cochrane databases using 'osteonecrosis of the jaw', 'jaw diseases', 'osteonecrosis', 'diphosphonate', 'biphosphonate' (amino-, alkyl- or the international nonproprietary name) as the main search items. The search was limited to English- and French-language articles published between 1966 and February 2010. Our search identified 27 cases of alkylbiphosphonate-induced ONJ in the literature. Among these cases, only ten patients were on alkylbiphosphonate monotherapy; in the other cases, aminobiphosphonates had also been used. The clinical presentation of the alkylbiphosphonate-induced ONJ was similar to that most often encountered with aminobiphosphonate treatment. The duration of exposure before onset was higher with alkylbiphosphonates than with aminobiphosphonates, and dental procedures before ONJ were frequent. Osteonecrosis of the jaw has been widely reported with various aminobiphosphonates, but data on the role of alkylbiphosphonates are scarce. As these latter drugs are less potent, a high cumulative dose through long-term exposure would appear to be necessary and would favour ONJ. Although the degree of risk for ONJ occurrence in patients on alkylbiphosphonates remains uncertain, it would be wise to reconsider carefully the indications for using these agents and to apply preventive measures as is currently done for aminobiphosphonates.

Survival of dental implants in post-menopausal bisphosphonate users

To determine whether post-menopausal women with a history of bisphosphonate use are at greater risk for implant failure or osteonecrosis of the jaw (ONJ) than an age- and gender-matched population with no history of bisphosphonate use. A retrospective chart review and phone interview was conducted of patients seen at the Mayo Clinic who had implants placed after November 2006. Bisphosphonate users were identified by medical chart review. Dental implant survival and ONJ incidence were determined in a total of 82 post-menopausal non-bisphosphonate users and 55 post-menopausal bisphosphonate users using a phone interview. Implant failures were recorded and survival percentages were calculated for comparison. ONJ was not observed consequent to implant placement in any of the bisphosphonate users or non-users. In non-users, 163 out of 166 implants were surviving for a cumulative survival rate of 98.19%. In bisphosphonate users, 120 out of 121 implants were surviving for a cumulative survival rate of 99.17%. Dental implants placed in post-menopausal women have the same survival potential regardless of whether patients have a history of bisphosphonate use. Bisphosphonate users who undergo dental implant surgery are at low risk for osteonecrosis of the jaw and a bisphosphonate "drug holiday" is not indicated in these patients.

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

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

Analysis of Bevacizumab (Bev) Therapy, Bisphosphonate Use and Osteonecrosis of the Jaw (ONJ) in &amp;gt;1900 Patients Treated in Two Randomized, Controlled Trials.

Abstract Background: Long-term bisphosphonate therapy is known to increase the risk of ONJ. A 16% incidence of ONJ was reported in a retrospective analysis of 116 patients receiving bisphosphonates with anti-angiogenic therapy (Bev or sunitinib) for bone metastases from breast, colon, or renal cell cancers.Methods: To assess the incidence of ONJ with Bev, we analyzed data from &amp;gt;3500 patients with locally recurrent or metastatic breast cancer (LR/MBC) treated in three large trials of Bev-containing therapy: AVADO (Bev in combination with docetaxel); RIBBON-1 (Bev in combination with taxane, anthracycline-based combination therapy, or capecitabine); and MO19391 (single-arm safety study of &amp;gt;2000 patients receiving Bev-containing therapy in the general oncology practice context). The incidence of ONJ was compared in patients treated with Bev versus placebo and in patients with or without bisphosphonate exposure.Results: Data from the blinded phase of two randomized, placebo-controlled trials demonstrated an ONJ incidence of 0.3%. ONJ was more common in patients who also received bisphosphonate therapy than in those who received no bisphosphonates (Table). This observation is supported by data from 2216 patients treated in the single-arm MO19391 study (2.4% with bisphosphonate versus 0% without). AVADO*RIBBON-1**TotalIncidence of ONJ, no. of pts (%)Bev (n=492)Pla (n=238)Bev (n=817)Pla (n=412)Bev (n=1309)Pla (n=650)Overall population receiving Bev (n=1309)3 (0.6%)O1 (0.1%)O4 (0.3%)OBisphosphonate (n=233)1 (1.2%)O1 (0.6%)O2 (0.9%)ONo bisphosphonate (n=1076)2 (0.5%)OOO2 (0.2%)O *Bev 15 and 7.5 mg/kg arms pooled**Taxane/anthracycline and capecitabine cohorts pooledConclusions: This is the largest analysis of ONJ in patients receiving Bev for LR/MBC. The 0.3% incidence of ONJ with Bev is considerably lower than previously reported by Christodoulou et al. with anti-angiogenic therapy. As in the general population, the risk of ONJ is increased in patients exposed to bisphosphonates. The 0.9–2.4% incidence seen here in a large population of patients receiving Bev and bisphosphonate therapy is substantially lower than the 16% observed in a small cohort of patients from a retrospective analysis and within the range reported in the literature for bisphosphonates alone (1–4%). Good oral hygiene, dental examination and avoidance of invasive dental procedures remain important in patients receiving bisphosphonates, irrespective of Bev treatment. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 208.

Longitudinal Cohort Study of Risk Factors in Cancer Patients of Bisphosphonate-Related Osteonecrosis of the Jaw

The reported incidence of osteonecrosis of the jaw (ONJ) ranges from 0.94% to 18.6%. This cohort study aimed to calculate the incidence of and identify the risk factors for ONJ in patients with cancer treated with intravenous zoledronate, ibandronate, and pamidronate. Data analyzed included age, sex, smoking status, underlying disease, medical and dental history, bisphosphonates (BP) type, and doses administered. Relative risks, crude and adjusted odds ratios (aORs), and cumulative hazard ratios for ONJ development were calculated. We included 1,621 patients who received 29,006 intravenous doses of BP, given monthly. Crude ONJ incidence was 8.5%, 3.1%, and 4.9% in patients with multiple myeloma, breast cancer, and prostate cancer, respectively. Patients with breast cancer demonstrated a reduced risk for ONJ development, which turned out to be nonsignificant after adjustment for other variables. Multivariate analysis demonstrated that use of dentures (aOR = 2.02; 95% CI, 1.03 to 3.96), history of dental extraction (aOR = 32.97; 95% CI, 18.02 to 60.31), having ever received zoledronate (aOR = 28.09; 95% CI, 5.74 to 137.43), and each zoledronate dose (aOR = 2.02; 95% CI, 1.15 to 3.56) were associated with increased risk for ONJ development. Smoking, periodontitis, and root canal treatment did not increase risk for ONJ in patients receiving BP. The conclusions of this study validated dental extractions and use of dentures as risk factors for ONJ development. Ibandronate and pamidronate at the dosages and frequency used in this study seem to exhibit a safer drug profile concerning ONJ complication; however, randomized controlled trials are needed to validate these results. Before initiation of a bisphosphonate, patients should have a comprehensive dental examination. Patients with a challenging dental situation should have dental care attended to before initiation of these drugs.

Risk of osteonecrosis of the jaw in cancer patients taking bisphosphonates

The risk of osteonecrosis of the jaw (ONJ) associated with bisphosphonate use in patients with cancer is reviewed. ONJ is a relatively new complication of supportive care in cancer. Bisphosphonate-associated ONJ can be generally defined as necrotic bone exposure to the oral cavity and inflammatory reactions of the surrounding soft tissue in patients receiving bisphosphonates but not radiotherapy to the head and neck. The risk of development of ONJ varies with the type of bisphosphonate used and the duration of exposure, with more potent agents increasing the risk with shorter durations of exposure. From the current evidence, the incidence of this disorder in cancer patients receiving bisphosphonates can be as high as 10% when patients have more than one risk factor. Risk factors include type of bisphosphonate, duration of exposure, concomitant medications, comorbidities (e.g., hypertension, dyslipidemia, diabetes, rheumatoid arthritis, lupus), and lifestyle behaviors (e.g., smoking, obesity). To minimize the risk of ONJ, patients initiated on bisphosphonates should optimize routine dental care and have their baseline oral cavity status evaluated by both clinical and radiographic examinations before initiation of bisphosphonate therapy. Current management of ONJ is difficult and empirical. At present, a conservative approach is recommended, including systemic antibiotics, antiseptic oral rinses, pain control, and limited debridement. Cancer patients receiving bisphosphonates are at risk for developing ONJ. Clinicians should evaluate patients' oral integrity and existing risk factors before initiating bisphosphonate therapy. Once treatment is started, patients should be closely monitored for signs and symptoms of ONJ.

Intravenous Bisphosphonate-Related Osteonecrosis of the Jaw: Bone Scintigraphy as an Early Indicator

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is recognized as a serious complication among patients receiving bisphosphonate therapy. However, methods for early detection and identification of patients at risk for osteonecrosis of the jaw (ONJ) need further investigation. The purpose of this study was to characterize BRONJ among patients receiving intravenous bisphosphonates and to examine bone scintigraphy findings that preceded manifestation of frank ONJ. We identified all known cases of BRONJ (defined according to 2006 American Association of Oral and Maxillofacial Surgeons criteria) diagnosed between January 2004 and September 2008 among patients who received intravenous bisphosphonate therapy (IVBP). The medical records were abstracted, and the clinical and radiographic features of BRONJ and relevant comorbidities were characterized. Technetium Tc 99 bone scintigrams were systematically reviewed among the subset of patients who received these imaging studies for oncologic care and imaging findings were correlated with the temporal development of ONJ. We identified 59 cases of intravenous BRONJ (median age, 61.4 +/- 10.7 years; 57.6% female), of whom 44.1% had breast cancer, 33.9% had multiple myeloma, and the remainder had metastatic prostate cancer (15.3%) or other cancers (6.8%). One third (32.2%) of the cohort was diabetic. In addition to IVBP, the vast majority (86.4%) had also received prior systemic glucocorticoid therapy. The median cumulative number of IVBP doses was 25 (interquartile range, 16-39) at the time of BRONJ diagnosis. Half of the patients had prior invasive dental procedures; ONJ developed spontaneously in 27.1%, and in the remainder ONJ developed in the setting of periodontal disease (10.1%) or local trauma (8.4%). Most patients presented with painful stage 2 disease involving the mandible (75%), and Actinomyces was present in more than 77% of available histologic specimens. During the median follow-up of 1.5 years, 15 patients (25.4%) regressed to a less severe stage, with healing in 6 patients; 16 (27.1%) worsened; and the remainder stayed within the same stage, but in almost half of these patients, the extent of involvement progressed. Of the 38 patients who had 99Tc bone scintigraphy, 35 had bone scans before development of BRONJ, and among these patients, 23 (67.5%) had positive tracer uptake in areas that subsequently developed BRONJ. In this study bone scintigraphy showed positive tracer uptake before the development of BRONJ in almost 66% of patients who had these scans before clinical evidence of frank osteonecrosis. BRONJ subsequently developed in the areas identified on scintigraphy in these patients. Further studies should explore the role of bone scintigraphy in the detection of early subclinical BRONJ.

Factors that determine survival among patients with multiple myeloma (MM) treated with zoledronic acid (ZOL)

e19519 Background: Although the overall survival of MM patients has improved with new treatment options, few studies have evaluated prognostic factors since these new therapies have become available. Monthly ZOL has been incorporated into many of these regimens to reduce skeletal complications. Side effects from ZOL have been reported but their frequency and outcomes have not been well-defined. This retrospective study aimed to identify key baseline and on-treatment prognostic factors among MM patients treated with ZOL. Methods: Three hundred patient charts were consecutively reviewed. Data was collected from the date of MM diagnosis to the date of chart review. Patient chart inclusion criteria required a diagnosis of MM and having received at least one dose of ZOL. Results: The median survival of among patients in this study was 131 months. Significant early risk factors for overall survival included skeletal-related events (SRE), increased serum creatinine, elevated serum calcium, and ISS Stage II or III at diagnosis. Fourteen patients (4.7%) developed osteonecrosis of the jaw (ONJ) after 9–96 months of ZOL treatment. Notably, there was a trend toward an increased risk of ONJ among diabetic patients. Thirteen patients with ONJ remain alive and currently are in remission or with stable disease. One patient with ONJ died while in remission from a myocardial infarction. Among the patients with a follow up of 4–49 months from the diagnosis of ONJ, 2 showed some worsening of this complication, 5 remained stable, while 7 improved or resolved. Patients with ONJ showed an improved overall survival using both landmark and time-dependent analysis. In addition, the overall skeletal morbidity rate (SMR; SREs/year) was 0.16. Notably, patients who developed ONJ had a lower SMR than among patients who did not develop ONJ. Conclusions: These results suggest that skeletal complications are an important prognostic factor for MM. Although ONJ occurs in MM patients, most patients show improvement with proper management and this complication appears to be associated with a reduced risk of SREs and improved overall survival. [Table: see text]