Diagnosis Of Osteonecrosis Of The Jaw Research Articles

Genome-wide association study of osteonecrosis of the jaw in Danish patients receiving antiresorptive therapy for osteoporosis: A case-control study

BackgroundPrior studies of the pharmacogenomics of osteonecrosis of the jaw (ONJ) have had various methodological limitations, including using candidate gene selection as their sole strategy, a small number of ONJ cases, or a study population based on an oncology setting. ObjectivesThe aim of our case-control study was to evaluate previously reported associations between genetic factors and ONJ, which were based on either genome-wide association studies (GWAS) or candidate gene approaches. Furthermore, we aimed to identify genetic risk factors for ONJ by using GWAS to determine single-nucleotide polymorphisms (SNPs) with statistically significant differences in frequency between ONJ patients and osteoporosis controls. MethodsPatients with medically confirmed ONJ and who were registered in the Scandinavian Cohort of ONJ patients were included. Controls from the general population were matched on age (±5 years), sex, and cumulative antiresorptive drug exposure. The ONJ diagnosis date for cases corresponded to the index date for matched controls. DNA isolation, genotyping, and data analyses were performed by Q2/EA Genomics using standard protocols and best practices. Blood or tissue samples for 55 ONJ cases and 125 controls were collected. Due to the low quality of the tissue samples, final analyses were based on blood samples of 40 ONJ cases and 124 controls. ResultsWe detected no significant genome-wide associations. Of the 43 SNPs with ONJ association in prior studies, none were replicated in our study. ConclusionsEven though our study sample is the largest to date, we had limited statistical power for GWAS but adequate power for replication analyses. Our study provides no evidence for any genetic predisposition to ONJ. Future studies could increase their statistical power by combining ONJ GWAS datasets and by performing a meta-analysis or pursuing a sequencing strategy in order to identify rare variants.

Understanding osteoporosis treatment drugs and jaw bone necrosis

Since the first report of osteonecrosis of the jaw (ONJ) associated with bisphosphonate (BP) administration in 2003, there have been many efforts to establish the pathophysiologic nature of this disease. Given that its pathogenesis is still poorly understood, and the global dependence on BP use and the entry tor aging society, there is a pressing need of related investigations. In this article, the authors aimed to assess the possible ONJinducing drug including BPs, Denosumab, Romosozumab, and etc., and investigate the actual diagnosis and treatment of ONJ.

Serum biomarkers for bisphosphonate-related osteonecrosis of the jaw: a prospective clinical study.

Bisphosphonate-related osteonecrosis of the jaw (ONJ) is an adverse effect of long-term bisphosphonate therapy. This study aimed to identify bone biomarkers for ONJ risk assessment and diagnosis. This prospective study included patients with histories of bisphosphonate therapy without current ONJ who were in need of dentoalveolar surgery of the jaw area. Serum levels of 12 possible bone markers, selected based on their involvement in ONJ pathogenesis, were compared between ONJ and control groups before dentoalveolar surgery (T0), at 8 postoperative weeks (T1), and at 4months after diagnosis(T2). Seventy-six patients who met the inclusion criteria were included in the study; 33 were assigned to the ONJ group, and 43 patients without ONJ signs or symptoms after dentoalveolar surgery were assigned to the control group. In the ONJ group, at both T0 and T1, the mean tartrate-resistant acid phosphatase isoform 5b (TRACP 5b) levels were significantly lower and the mean Dickkopf-related protein 1 (DKK1) levels were significantly higher than the corresponding values for the control group. Linear mixed model analysis revealed significant group effects over time for serum TRACP 5b and DKK1 after adjusting for demographic, pharmacological, and diagnostic variables. Lower serum levels of TRACP 5b under a specified cut-off value (≤ 2.899 U/L) at T0 indicated a 20.40-fold increased risk of ONJ development. Patients with abnormally low serum levels of TRACP 5b and high serum levels of DKK1 should be monitored closely before and after dentoalveolar surgery for the prevention and early diagnosis of ONJ.

Osteonecrosis of the jaw in metastatic renal cell carcinoma (mRCC) patients treated with zolendronic acid and denosumab: An observational retrospective multicenter trial.

299 Background: Bone is one of the most common site of metastasis occurring in 30% of metastatic renal cell carcinoma (mRCC) patients (pts)3,4. Skeletal metastases from mRCC are usually osteolytic and associated to high rate of morbidity and complication through skeletal related events (SRE). Bone-targeted therapies (BTT) such as zolendronic acid (ZOL AC) and denosumab (Dmab), shown to decrease the time-to-first and subsequent SREs12. Osteonecrosis of the jaw (ONJ) is a rare but potentially serious adverse event associated with BTT. It occurs in 1-2% of pts treated with BTT and in 10-17% of mRCC pts treated with ZOL AC or Dmab. Vascular endothelial growth factor-Tyrosine kinase inhibitors (VEGF-TKI) represent the backbone treatment for mRCC. Nevertheless, it is unclear whether the association of DMAB and ZOL AC to VEGF-TKITTagents could be associated to higher incidence of ONJ. Methods: We retrospectively collected data, from 2 Italian referring centers for mRCC, about 74 pts with bone metastases from mRCC who received, concurrently or sequentially to VEGF-TKI or immune-oncology (IO), AC ZOL and DMAB from January 2013 to January 2020. All pts provided informed consent for inclusion in the study. Results: All pts received VEGF-TKI as first line treatment. 17 pts received AC ZOL whereas 57 received DMAB. All pts received odontological consultation and orthopantomography before start BTT. The median time of Dmab and AC ZOL exposure was 11.6 months. ONJ occurred in 10/74 pts (7.4%): 6/10 pts were on first line treatment and 4/10 on second line. Treatments administered at the time of ONJ diagnosis were nivolumab (1/10), cabozantinib (2/10), sorafenib (1/10), sorafenib (1/10), sunitinib (4/10) and one pts was off therapy. Conclusions: In this real-life Italian population, treatment with BTT in mRCC pts treated with VEGF-TKI inhibitors and IO is associated to higher incidence of ONJ compared to previous report of pts treated with BTT for bone metastasis and lower compared to previous reports in mRCC. Despite the retrospective collection, we provided one of the largest sample of pts treated concurrently with VEGF-TKI or IO and BTT. Physicians should be careful in the use of BTT combined with other treatments in mRCC pts.

Risk of Osteonecrosis of the Jaw Under Denosumab Compared to Bisphosphonates in Patients With Osteoporosis.

Osteonecrosis of the jaw (ONJ) is a rare but serious adverse event associated with antiresorptive treatment. There is little evidence regarding the incidence of ONJ among patients with osteoporosis who are treated with denosumab versus bisphosphonates (BPs). The aim of this study was to determine the risk of ONJ in a real-world population. Subjects who underwent at least one dual-energy X-ray absorptiometry (DXA) examination were included in the osteoporosis register of the Swiss Society of Rheumatology between January 1, 2015, and September 30, 2019. Statistical analyses included incidence rates, rate ratios, and hazard ratios for ONJ, considering sequential therapies and drug holidays as covariates. Among 9956 registered patients, 3068 (89% female, median age 69 years [63 to 76]) were treated with BPs or denosumab for a cumulative duration of 11,101 and 4236 patient-years, respectively. Seventeen cases of ONJ were identified: 12 in patients receiving denosumab at the time of ONJ diagnosis and 5 in patients receiving oral or intravenous BP therapy. The diagnosis of ONJ was confirmed by independent and blinded maxillofacial surgeons, using the American Association of Oral and Maxillofacial Surgeons case definition of ONJ. The incidence of ONJ per 10,000 observed patient-years was 28.3 in patients receiving denosumab and 4.5 in patients with BP-associated ONJ, yielding a rate ratio of 6.3 (95% confidence interval [CI] 2.1 to 22.8), p < 0.001. Nine of 12 patients who developed ONJ during denosumab treatment had been pretreated with BPs, but none of the 5 patients with BP-related ONJ had previously received denosumab. The risk of ONJ was higher in patients receiving denosumab therapy compared with BPs (hazard ratio 3.49, 95% CI 1.16 to 10.47, p=0.026). Previous BP therapy before switching to denosumab may be an additional risk factor for ONJ development. © 2021 American Society for Bone and Mineral Research (ASBMR).

Drug holiday patterns and bisphosphonate-related osteonecrosis of the jaw.

There is limited evidence regarding the appropriate length of a bisphosphonate (BP) holiday to reduce the risk of osteonecrosis of the jaw (ONJ). In this cross-sectional study, we investigated the population-based patterns of the gaps between BP discontinuation and ONJ diagnosis. We used the claims database of the National Health Insurance Service in Korea. Among BP users between 2006 and 2015, incident ONJ cases during 2010-2015 with no history of ONJ in the last 4years were identified. We assessed the time gap from the last BP administration to ONJ diagnosis. Among 1,569 incident ONJ cases, 836 (53.3%) occurred after BP discontinuation. The cumulative proportions of ONJ occurrence within 1month, 3months, 1year, 2years, and 3years after discontinuation were 58.9%, 70.8%, 87.0%, 93.2%, and 96.1%, respectively. The length of drug holidays showed no significant difference between patients with or without comorbid cancer and diabetes mellitus (p-value, 0.12 and 0.52, respectively). However, the use of injectable BP formulations significantly affected ONJ incidence (p<0.01). Most ONJ cases occurred within 3years from BP suspension, with a higher prevalence among BP injection users with 1year or lesser BP holiday.

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 and survival of patients with cancer: a nationwide cohort study in Denmark.

Osteonecrosis of the jaw (ONJ) is an adverse effect of bone‐targeted therapies, which are used to prevent symptomatic skeletal events following bone malignancy. We examined the association between ONJ and survival among cancer patients treated with bone‐targeted agents. Using nationwide registries and databases in Denmark, we identified 184 cancer patients with incident ONJ between 2010 and 2015, and a comparison cohort of 1067 cancer patients without ONJ and with a history of hospital‐administered treatment with bisphosphonates or denosumab initiating from cancer diagnosis. At the date of confirmed ONJ diagnosis, the comparison cohort was matched to the ONJ patients on age, cancer site, year of cancer diagnosis, and stage at diagnosis. The patients were followed up for survival until emigration or 15 June 2016. We computed overall survival and estimated mortality rate ratios adjusted for sex, and for the presence of distant metastases and other comorbidity at start of follow‐up. A match was found for 149 of the 184 ONJ patients. The 1‐ and 3‐year survival among all 184 cancer patients with ONJ was 70% (95% confidence interval [CI]: 63%–76%) and 42% (95% CI: 34%–51%), respectively. Among the matched patients, ONJ was associated with an adjusted mortality rate ratio of 1.31 (95% CI: 1.01–1.71). ONJ was associated with reduced survival among cancer patients treated with bone‐targeted agents. ONJ may be a marker of advanced disease or of survival‐related lifestyle characteristics.

Drug-induced osteonecrosis of the jaw: the state of the art.

Osteonecrosis of the jaw (ONJ) is a rare adverse event of antiresorptive drugs such as bisphosphonates (BP) and denosumab (DMAb). The diagnosis of ONJ is considered in cases where exposed bone in the maxillofacial region does not heal within 8 weeks in a patient previously treated with an antiresorptive agent. In patients with osteoporosis, ONJ is reported as a very rare adverse event while in oncologic patients with bone metastases or malignant hypercalcemia the incidence is significantly higher (up to the 1-10% of the patients). The pathophysiology of ONJ is still not completely understood but it is multi-factorial. ONJ is a condition associated with poor oral health, oral surgery, and use of antiresorptive agents. Prevention is of paramount importance especially in cancer patients, in whom the large majority of cases of ONJ (&gt;90%) are reported, but it should also be considered in osteoporotic patients, especially during dental surgical procedure. Some simple prevention procedures are effective in reducing the risk of its appearance. When ONJ unfortunately occurs, the large majority of patients can be managed conservatively. In conclusion, ONJ is a rare condition associated with antiresorptive drugs. Both osteoporotic and oncologic patients should be well informed about its low absolute risk and regarding the fact that the benefits of antiresorptive therapy far outweigh this potential risk of ONJ.

Osteonecrosis of the jaw (ONJ): diagnosis and management in 2015.

Osteonecrosis of the jaw (ONJ) has been associated with the use of aminobisphosphonates and denosumab. The vast majority (>90%) of cases occur in the oncology patient population receiving high doses of intravenous bisphosphonates or subcutaneous denosumab. The incidence of ONJ in the osteoporosis patient population is very low and is estimated at 1-90 per 100,000 patient-years of exposure. In the oncology patient population the incidence appears to be related to dose and duration of exposure, and prevalence has been estimated to be as high as 18.6%. A number of risk factors in addition to antiresorptive therapy have been identified. These include the presence of periodontal disease, oral surgical procedures with extractions or implants, radiation therapy, chemotherapy, diabetes, glucocorticoid use, and smoking. Antiangiogenic agents appear to contribute to the risk of ONJ, however, data at this time are limited and further evidence is required prior to confirming a causal relationship. ONJ may be prevented with optimization of oral hygiene, the use of oral antimicrobial mouth rinses, as well as systemic antibiotic therapy. Individuals not responding to conservative management or in the advanced stages of ONJ may be considered for surgery, as data over the past several years have demonstrated surgical success in this patient population. Case reports have indicated that teriparatide may enhance healing. A number of experimental therapies are being evaluated and include the use of bone marrow stem cell intralesional transplantation, local application of platelet-derived growth factor, hyperbaric oxygen, tissue grafting, and low-level laser therapy. This paper summarizes the current research as well as the international consensus on the diagnosis and management of ONJ.

Bone and Calcium Metabolisms Associated with Dental and Oral-Maxillofacial Diseases. Destructive bone resorption by osteoclasts and oral disease

Osteoclasts are multinucleated cells that resorb bone, originate from monocyte-macrophage lineage cells. Periodontitis is an inflammatory disease characterized by destruction of periodontal tissues including alveolar bones. Oral implant system is established average dental treatment method. However, peri-implantitis affects the convalescence. Osteonecrosis of the jaw (ONJ) is also inflammatory disease associated with antiresorptive therapy of bisphosphonates. Diagnosis and management of ONJ is more important issue.

Periodontal disease preceding osteonecrosis of the jaw (ONJ) in cancer patients receiving antiresorptives alone or combined with targeted therapies: report of 5 cases and literature review

We present clinical and radiologic data of periodontal tissue involvement preceding the appearance of osteonecrosis of the jaw (ONJ) in 5 patients with solid tumors, who received antiresorptives alone or in combination with targeted therapies. Five patients with osteonecrosis before dental extraction were studied. Periodontal involvement was evidenced by pain, bleeding, fistula, purulence, swelling, periodontal pocket, and tooth mobility. Combined endoperiodontal lesions were considered in 1 patient. Duration of symptoms before ONJ diagnosis lasted 8 to 24 weeks. Routine therapy was performed in 2 of 5 patients. Widening of the periodontal ligament was observed in 4 patients, and dense alveolar bone was seen in 1 patient. Local complications of ONJ required dental extractions in 4 of 5 patients. Spontaneous tooth exfoliation was observed in 1 patient. Alveolar bone biopsies, after the extraction in 2 patients, confirmed osteonecrosis. Osteonecrosis healed in 2 patients--1 after the dental extraction and 1 after 3 dental extractions and surgical debridement. Postextraction socket healed in 1 patient, and the area with exposed bone remained asymptomatic. Osteonecrosis progressed in 2 patients. Clinical and radiologic signs of periodontal tissue involvement, before dental extraction in patients treated with antiresorptives alone or in combination with targeted therapy, may represent developing osteonecrosis.

Evaluation of an ICD-10 algorithm to detect osteonecrosis of the jaw among cancer patients in the Danish National Registry of Patients.

This study aimed to validate a predefined algorithm for osteonecrosis of the jaw (ONJ) among cancer patients in the Danish National Registry of Patients and to assess the nature of clinical information recorded in medical charts of ONJ patients. We identified potential ONJ cases recorded in 2005-2010 among cancer patients at the hospital Departments of Oral and Maxillofacial Surgery (DOMS) in three Danish regions, using a set of codes from the International Classification of Diseases, 10th revision (ICD-10). We abstracted DOMS charts of the potential cases, had the ONJ status adjudicated by an expert ONJ adjudication committee (ONJAC), and computed positive predictive values. For patients with ONJAC-confirmed ONJ, we abstracted the charts for information on ONJ clinical course. Sensitivity of the algorithm was computed using a separate sample of 101 known ONJ cases accrued in 2005-2011. We identified 212 potential ONJ cases, of which 197 (93%) had charts available for abstraction. Eighty-three potential cases were confirmed by ONJAC, with a positive predictive value of 42% (95% confidence interval [CI] 35%-49%). DOMS charts of these 83 cases contained complete information on ONJ clinical course. Information about antiresorptive treatment was recorded for 84% of the patients. Among the 101 known ONJ cases, 74 had at least one prespecified ICD-10 code recorded in the Danish National Registry of Patients within ±90 days of the ONJ diagnosis (sensitivity 73%; 95%CI [64%-81%]). The predefined algorithm is not adequate for monitoring ONJ in pharmacovigilance studies. Additional case-finding approaches, coupled with adjudication, are necessary to estimate ONJ incidence accurately.

Risk factors influencing the duration of treatment with bisphosphonates until occurrence of an osteonecrosis of the jaw in 963 cancer patients

Osteonecrosis of the jaw (ONJ) is an adverse effect that is associated with bisphosphonate (BP) use. Little data are available on risk factors influencing the time of treatment until an osteonecrosis occurs. From 1 Dec 2004 until 21 Sep 2012, the German Register collected all patients with validated diagnoses of ONJ (N = 1,229) that were reported to the national pharmaco-vigilance system or to the Register directly. We analysed 963 patients with cancerous disease and an ONJ during i.v. BP treatment. Duration of BP treatment until first diagnosis of ONJ and Kaplan-Meier curves of ONJ-free survival were analysed stratified by gender, type of BP and type of cancer. Main indications for BP treatment were breast cancer (36%), multiple myeloma (24%), prostate cancer (16%) and kidney cancer (4%). Men suffered from their ONJ earlier than women. A total of 780 patients (81%) had their ONJ during zoledronate treatment, 93 (10%) under pamidronate and 90 (9%) under ibandronate treatment. ONJ-free survival in single BP users was significantly longer in pamidronate-treated patients than in zoledronate or ibandronate users. Ibandronate users had the shortest median duration of treatment (17 months), similar to that of zoledronate users (21.5 months). Sequential prescription of two different BPs prolonged the period of overall BP treatment until an ONJ occurred. Time of BP treatment was shortest in patients with kidney cancer. Age or a concomitant osteoporosis did not influence the time to event of an ONJ. Systemic risk factors such as gender play a significant role in certain subgroups only. Comparative analysis of different cancer patients helps the treating oncologist/dentist to identify patients with a more imminent risk to develop an ONJ (i.e. kidney cancer, ibandronate/zoledronate use).

Dentistry for osteoporosis and cancer patients

Bisphosphonates (BPs) and similarly acting bone antiresorptive agents such as denosumab are becoming the principal if not sole therapeutic agents for the preventative treatment against fracture occurrence in osteoporosis (OP) patients. BPs are also increasingly used in the treatment of severely painful and potentially life-shortening bone complications, including fracture occurrence, in cancer patients. Are we seeing not only a rapid expansion of research focused on the prevention and treatment of osteonecrosis of the jaw (ONJ) but also the emergence of a new sub-specialty focusing on the diagnosis, prevention and treatment of ONJ?

Incidence and risk of osteonecrosis of the jaw among the Taiwan osteoporosis population

Evidence of the incidence and risk of osteonecrosis of the jaw (ONJ) in Asian osteoporosis populations receiving different osteoporosis medications is lacking. We found that there is no excess incidence of or risk for ONJ in osteoporosis patients >50 years old using alendronate as compared with patients using raloxifene or calcitonin under real-world conditions in Taiwan. To provide information on ONJ in Asian populations, this study compares the incidence and risk of ONJ between patients receiving alendronate and those receiving non-bisphosphonate osteoporosis medications in Taiwan. Enrollees in the National Health Insurance Research Database (NHIRD) from 2003 to 2007, aged above 50 years, with vertebral/hip fracture, and new to osteoporosis therapy were recruited. Patients with Paget's disease or cancer during the baseline period were excluded. Patients were classified into either the alendronate or the calcitonin/raloxifene (control) group according to their exposure during follow-up. Previously proposed possible ONJ diagnosis codes were adopted as potential ONJ cases, but qualifying cases also had a repeated ONJ diagnosis within 8 weeks of the first diagnosis and received one or more broad-spectrum oral antibiotics. Cox modeling compared the risk of ONJ between the alendronate and the control groups, which were matched using propensity scores. Results were examined in series sensitivity analyses, including different cumulative dose groups. We found 25 potential ONJ cases in the alendronate (N = 18,030) and 21 in the control groups (N = 25,615). Over the 6-year follow-up period, no increased risk of ONJ in the alendronate group in the original (hazard ratio (HR), 0.87; 95% confidence interval (CI), 0.47-1.58) or propensity score-matched cohorts (HR, 0.86; 95% CI, 0.44-1.69) was found. All comparison groups exhibited a similar incidence of ONJ, ranging from 6.9 to 8.2/10,000 person-years. Under real-world conditions, there is no excess risk for ONJ in osteoporosis patients >50 years old using alendronate as compared with patients using raloxifene or calcitonin.

Clinical study evaluating the effect of bevacizumab on the severity of zoledronic acid-related osteonecrosis of the jaw in cancer patients

This study aimed to evaluate the effect of bevacizumab (BVZ) on the severity of osteonecrosis of the jaw (ONJ) in a cohort of cancer patients treated with intravenous zoledronic acid (ZA). We reviewed 42 oncologic patients with ONJ between 2007 and 2010. Only patients with solids tumors and who had received ZA were included. Data analyses included age, sex, underlying disease, ZA and BVZ dosages, dental history and ONJ characteristics. Of the 42 ONJ patients treated with ZA, 10 also received BVZ. In the 10 ZA/BVZ patients, the mean duration of ZA treatment at the time of ONJ diagnosis was 12.4months (±6.8), compared to 22.9months (±4.8) in the 32 patients who received ZA only (p<0.05). Cox's model analysis of the delay to ONJ diagnosis confirmed the impact of BVZ on ONJ diagnosis. In the ZA/BVZ-treated group, 7 (70%) patients developed spontaneous osteonecrosis. Multiple logistic regression analysis showed that ZA/BVZ is associated with increased risk of developing spontaneous ONJ (OR 6.07; 95% CI, [1.3–28.2], p<0.05). And finally, the number of ONJ lesions was increased in the ZA/BVZ-treated group compared to the ZA group (p<0.01). Other clinical conditions as type of tumor (prostate, breast…), cancer severity or other chemotherapy drugs also could be involved in ONJ evolution. However, this study demonstrates for the first time the potential negative influence of BVZ on the incidence and severity of ONJ in patients receiving ZA. Within the study limits, our results suggest that combination ZA/BVZ treatment may possibly predispose to the development of spontaneous and earlier ONJ.

Osteonecrosis of the Jaw and Oral Health–Related Quality of Life After Adjuvant Zoledronic Acid: An Adjuvant Zoledronic Acid to Reduce Recurrence Trial Subprotocol (BIG01/04)

In patients with early breast cancer, adjuvant zoledronic acid (zoledronate) may reduce recurrence and improve survival. However, zoledronate is associated with the occasional development of osteonecrosis of the jaw (ONJ). We report on the frequency of ONJ and investigate oral health-related quality of life (Oral-QoL) in a large randomized trial (Adjuvant Zoledronic Acid to Reduce Recurrence [AZURE]). Three thousand three hundred sixty women with stage II or III breast cancer were randomly assigned to receive standard adjuvant systemic therapy alone or with zoledronate administered at a dose of 4 mg for 19 doses over 5 years. All potential occurrences of ONJ were reported as serious adverse events and centrally reviewed. Additionally, we invited 486 study participants to complete the Oral Health Impact Profile-14 (OHIP-14) to assess Oral-QoL around the time the patients completed 5 years on study. Multivariable linear regression was used to calculate mean scores and 95% CIs in addition to identifying independent prognostic factors. With a median follow-up time of 73.9 months (interquartile range, 60.7 to 84.2 months), 33 possible cases of ONJ were reported, all in the zoledronate-treated patients. Twenty-six cases were confirmed as being consistent with a diagnosis of ONJ, representing a cumulative incidence of 2.1% (95% CI, 0.9% to 3.3%) in the zoledronate arm. Three hundred sixty-two patients (74%) returned the OHIP-14 questionnaire. Neither the prevalence nor severity of impacts on Oral-QoL differed significantly between zoledronate patients and control patients. Adjuvant zoledronate used in the intensive schedule studied in the AZURE trial is associated with a low incidence of ONJ but does not seem to adversely affect Oral-QoL.

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.

Dual antiangiogenic therapy using lenalidomide and bevacizumab with docetaxel and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC).

4569 Background: Previously, we had shown the potent anti−tumor activity of dual anti-angiogenic therapy by combining bevacizumab (B) and thalidomide (T) with docetaxel (D) and prednisone (P) in mCRPC (Ning JCO 2010). We hypothesized that combining lenalidomide (L), an analogue of T, with B, D, and P would have a more favorable efficacy/toxicity profile. Methods: All patients (pts) had chemotherapy−naïve mCRPC. Among the first 52 pts, 3 received L 15 mg daily, 3 had 20 mg daily, and the rest had 25 mg daily for 14 days of every 21−day cycle (C). The protocol was recently amended to enroll 11 more pts at L 15 mg; 2 pts have now been enrolled in this expansion cohort. All pts received D 75 mg/m2 and B 15 mg/kg on day 1 with P 10 mg and enoxaparin daily throughout each C. Pegfilgrastim was given on day 2. PSA each C with imaging after C2 and after every 3C. Dental exams with mandible CT scan at baseline, after C5, and every 6C. Results: 54 of 62 pts have been enrolled. Median age 65.5 (51−82), Gleason score 8 (5−10), on−study PSA 85.2 ng/ml (0.15−3520), and pre−study PSA doubling time 1.49 months (0.52−6.73). Median number of Cs was 16 (3−38). PFS was 22 months and probability of survival at 12 months was 90%. Forty-six (85.2%) and 42 (77.8%) pts had PSA declines of ≥50% and ≥75%, respectively. Of 30 pts with measurable disease there were 1 CR and 25 PR (86.7% overall RR). 17/54 pts were off study for radiographic disease progression and 8/54 for other reasons. Grade ≥2 toxicities included neutropenia (34/54), anemia (23/54), thrombocytopenia (7/54), hypertension (12/54), perianal fistula (3/54), rectal fissure (1/54), myocardial infarction (1/54), and osteonecrosis of the jaw (ONJ) (12/54, 22.0%). At the time of diagnosis of ONJ, 7/12pts were on bisphosphonates (BP), 2/12 had used BP previously, and 3/12 never used BP. The incidence of ONJ was comparable to 18.3% reported by Ning et al. A recent study of carboplatin plus weekly docetaxel reported an incidence of 29.3%. Conclusions: Dual anti-angiogenic therapy with, B and L, plus D and P was associated with high PSA (85.2%) and tumor (86.7%) responses in mCRPC, with manageable toxicities. The incidence of ONJ is comparable to other studies.