Osteonecrosis of the jaw in cancer patients receiving IV bisphosphonates

Cases of osteonecrosis of the jaw (ONJ) have been reported with an increasing frequency over the past few years. ONJ is most often identified in patients with cancer who are receiving intravenous bisphosphonate therapy but it has also been diagnosed in patients receiving oral bisphosphonates for nonmalignant conditions. The condition involves exposed bone of the maxilla or mandible. Although it is often associated with a recent dental surgical procedure, spontaneous ONJ can also occur. Patients commonly present with symptoms. Through case reporting and clinical experience, there is a suggestion that the incidence of ONJ in patients with cancer receiving intravenous bisphosphonates ranges between 1% and 10%. Management of ONJ focuses on maximizing oral health, conservative actions with mouth rinses, antibiotics, and avoidance of unnecessary invasive dental procedures. The currently available data on ONJ are reviewed here.     

Osteonecrosis of the jaw and use of bisphosphonates in adjuvant breast cancer treatment: a metanalysis

To estimate the cumulative randomized evidence for the overall incidence of bisphosphonates induced jaw osteonecrosis in adjuvant treatment of breast cancer. Systematic review and meta-analysis of randomized clinical trials. Trials were located through PubMed, ISI, Cochrane Library, and major cancer scientific meetings searches. We identified 15 studies reporting data on osteonecrosis of the jaw. A total of 10,694 randomized women were included, of whom 5,312 received bisphosphonates and 5,382 received either placebo or no treatment. Osteonecrosis of the jaw was a rare event, occurring in 13 (0.24%) of the 5,312 patients receiving bisphosphonates, and in one of the 5,382 patients in the control group. All the 13 events of osteonecrosis of the jaw reported among bisphosphonates arms occur in patients undergoing treatment with zoledronic acid (13/3,987, 0.33%). No events of osteonecrosis of the jaw were reported among patients randomized to receive clodronate (n = 669), pamidronate (n = 460), risedronate (n = 171), and ibandronate (n = 25); however, these samples were too small to be able to rule out the condition. Treatment with zoledronic acid was significantly associated to the occurrence of osteonecrosis of the jaw (OR = 3.23, 95% CI = 1.7–8) compared with no use. No significant between-study heterogeneity was observed. Despite use of zoledronic acid is associated to a higher number of events compared with no use, the osteonecrosis of the jaw during the adjuvant treatment of breast cancer is a rare event. At current dosage, adjuvant use of bisphosphonates in breast cancer treatment is safe. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Osteonecrosis of the jaw related to the use of bisphosphonates

PURPOSE OF REVIEW: Osteonecrosis of the jaw associated with the use of potent nitrogen containing bisphosphonates is a new and challenging clinical entity with a high impact on quality of life. This review attempts to consolidate the rapidly expanding literature into practical guidelines and provides expert consensus for areas of uncertainty. RECENT FINDINGS: Diagnostic criteria and a staging system for osteonecrosis of the jaw have been proposed, and histomorphologic analysis has confirmed osteonecrosis of the jaw as a proper disease, distinctively different from osteoradionecrosis. Various guidelines for the management of osteonecrosis of the jaw have been suggested and further retrospective research has provided new insights into its epidemiology. SUMMARY: Osteonecrosis of the jaw is a distinct entity of uncertain origin that is increasingly being observed in patients treated with potent aminobisphosphonates, although the etiology is probably multifactorial. Recent data confirm the predisposition of multiple myeloma patients to develop osteonecrosis of the jaw. Although various treatment strategies have been reported, conservative management remains the mainstay of therapy.     

Osteonecrosis of the jaw: dental outcomes in metastatic breast cancer patients treated with bisphosphonates with/without bevacizumab

The etiology, optimal management, and outcome of osteonecrosis of the jaw (ONJ) are not well understood. Because healing after mucosal trauma requires revascularization, theoretically, the combination of bevacizumab (bev) and a bisphosphonate (BP) could affect the time to development of ONJ and/or the response to dental therapy. We reviewed all cases of ONJ in metastatic breast cancer patients treated at our institution with bev+BPs and BPs alone between October 2002 and April 2010. We identified 27 ONJ patients with a median age of 57 years (range, 40 to 68 years). Seven patients received bev+BPs; 20 patients received BPs alone. Patients received intravenous zolendronate (95%), pamidronate (20%), or both (15%). Patients were treated with antibiotics (93%), alveoplasty/debridement (67%), and chlorhexidine scrub (81%). There was no difference in dental treatment between the groups or by the year of diagnosis (before 2007 versus 2007-2010). Complete resolution (CR) was achieved in 24% of all patients; 33% treated with bev+BPs, and 21% treated with BPs alone. Rates of CR improved from 15% to 33% after 2007. The median time to response was 5.6 months (range, 1.3 to 67.5 months). The addition of bev to BPs did not appear to alter the time to development of ONJ (32.6 months versus 34.6 months, respectively). The number of BP treatments administered before the diagnosis of ONJ between bev+BPs and BPs (32 doses versus 36.5 doses) was similar. However, our sample size was too small to characterize the difference statistically. Because dental management of ONJ has not changed over time at our institute, early recognition and screening may account for the improvement in dental outcomes.     

Osteonecrosis of the jaw in patients with bone metastases treated with bisphosphonates: a retrospective study

OBJECTIVE: Bone metastases are a major cause of morbidity in cancer patients. Treatment includes bisphosphonates, which are also associated with avascular osteonecrosis of the jaw (ONJ). Our aim was to evaluate the correlation between bisphosphonates and ONJ. PATIENTS AND METHODS: Of the 539 patients with bone metastases treated in our department from June 2002 to December 2006 with i.v. bisphosphonates, eight (1.5%) developed ONJ. RESULTS: The eight patients with ONJ had all been given zoledronic acid, and two had also been treated with pamidronic acid. In four of the patients, ONJ was diagnosed during treatment, while in the remaining four it was diagnosed several months after therapy with bisphosphonates had ended. Six of these patients received local noninvasive treatment, of whom five progressed. Two showed apparent autolimitation of the disease. The remaining two patients underwent surgical resection and currently show no signs of relapse. All eight ONJ patients presented with various concomitant risk factors such as paradontopathy, dental extraction, or spontaneous avulsion. CONCLUSIONS: Our results show that ONJ can appear months after interruption of treatment and that a surgical approach can be used in suitable cases. Closer cooperation is needed among specialists to define guidelines for the prevention of ONJ in patients with bone metastases.     

Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates: definition and management of the risk related to zoledronic acid

PurposeBisphosphonates (BPs) are currently used to treat bone lesions in patients with multiple myeloma (MM). Osteonecrosis of the jaw (ONJ) has been reported as an adverse event of such treatment, especially after treatment with zoledronic acid (ZA). The aim of this study was to evaluate incidence, risk factors, management, and prevention strategies of ONJ in order to optimize the current standard use of BPs in MM.Patients and MethodsWe reviewed the medical records of 105 patients with MM treated in 2 hematology departments with monthly pamidronate 90 mg and/or ZA 4 mg and evaluated for ≥ 12 months. Because they are risk factors for ONJ development, we analyzed patient and disease features, previous MM treatments, type and number of BP infusions, and previous history of dental procedures.ResultsSeventeen patients (16%) with MM treated with BPs developed ONJ after a median number of 43 BP infusions (vs. 28 in patients without ONJ; P = .035). In 11 of 17 patients, ONJ arose after a tooth extraction. Among risk factors, the administered doses of ZA were significantly associated with ONJ, and 12 consecutive doses of ZA proved to double the risk of developing this complication. Regular hard- and soft-tissue oral assessment was of benefit in the prevention of further ONJ occurrence.ConclusionThe most important risk factor for ONJ is represented by the number of ZA infusions. Tooth extractions and invasive procedures should be avoided. A multidisciplinary approach including oncohematologists and dental teams proved critical to better identify, prevent, and manage ONJ.     

Osteonecrosis of the jaw and bisphosphonate use in breast cancer patients

It is renowned that breast cancer patients suffer from a number of cancer-related skeletal events, while drugs recently added to the practitioners’ quiver, such as aromatase inhibitors, intensify the need to preserve bone mass in this group of patients. Bisphosphonates are potent inhibitors of both normal and pathologic bone resorption. Besides their apoptotic and antiproliferative activity on osteoclasts, bisphosphonates can also exert various effects on macrophages, keratinocytes and fibroblasts. Bisphosphonate-related osteonecrosis of the jaw is a complication that emerged after broad clinical use of bisphosphonates, and which has not yet been adequately described in a clinical trial setting. The purpose of this review is to critically reflect the incidence, etiopathogenesis, prevention and treatment of osteonecrosis of the jaw. Succinct suggestions are provided to ensure clinicians prevent and detect the complications early.     

Thrombosis and breast cancer: incidence, risk factors, physiopathology and treatment

Breast cancer is associated with a low rate of thromboembolic events (TEE) when compared to other cancers, without influence of the histological type on incidence. Risk factors include the stage of cancer, and the patients' profile and management: hospitalization, surgery and presence of a central catheter but also some cytotoxic chemotherapy, tamoxifen, and some anti-angiogenic targeted therapies. The pathophysiology of TEE includes a cross-stimulation phenomenon, involving tumor cells with procoagulant activity, and factors of hemostasis, coagulation and fibrinolysis. Circulating cellular microparticles bearing tissue factor play a major role, as well as thrombogenic platelet interactions with tumor cells via P-selectin. The occurrence of TEE in a cancer patient significantly increases the risk of death. Prevention is framed by recommendations in surgical patients. Curative treatment is based on the use of low molecular weight heparin for at least six months.     

乳腺癌相关淋巴水肿发病情况及危险因素前瞻性队列研究

目的 明确乳腺癌患者术后2年内上肢淋巴水肿的发病率及其危险因素。方法 对157例初诊手术治疗的乳腺癌患者进行随访,采用诺曼问卷和周径测量法分别在术前和术后1、3、6、12、18、24个月评估患者上肢体积变化情况,计算淋巴水肿发病率。并以周径测量法结果为基础行Logrank单因素分析和Cox模型多因素分析。结果 有效数据141例,术后1、3、6、12、18、24个月诺曼问卷调查的发病率分别为3.5%、9.2%、13.5%、24.8%、28.4%、30.5%,周径测量法结果为1.4%、3.5%、9.2%、20.6%、27.0%、27.7%。术后24个月39例淋巴水肿患者中31例为轻度水肿。腋窝淋巴结清扫(HR=13.58,95% CI∶2.17~85.00)、放疗(HR=3.54,95% CI∶1.13~11.07)、改良根治术(HR=2.19,95% CI∶1.07~4.49)、腋窝淋巴结清扫数目(HR=1.11,95% CI∶1.05~1.16)是危险因素。结论 乳腺癌相关淋巴水肿在术后2年内发病率逐渐上升,尤以第1年为甚。腋窝淋巴结清扫、放疗、改良根治术和腋窝淋巴结清扫数目为危险因素。     

双磷酸盐药物所致下颌骨坏死研究进展

下颌骨坏死是一种罕见的并发症,被报道曾发生于接受过放疗、化疗及其他肿瘤治疗等多种治疗方法的癌症患者.双磷酸盐是一种强有力的破骨细胞抑制剂,主要用于Paget's病、骨质疏松症、多发性骨髓瘤、恶性肿瘤高钙血症、乳腺癌和前列腺癌骨转移.近年来,有关含氮双磷酸盐(帕米磷酸和唑来磷酸)相关性骨坏死的报道日渐增多,其作用机理目前尚不明确.现就双磷酸盐药物致下颌骨坏死的可能作用机制、临床表现、诊断、治疗及预防等相关内容作一综述.     

双磷酸盐药物所致下颌骨坏死研究进展

下颌骨坏死是一种罕见的并发症,被报道曾发生于接受过放疗、化疗及其他肿瘤治疗等多种治疗方法的癌症患者.双磷酸盐是一种强有力的破骨细胞抑制剂,主要用于Paget＇s病、骨质疏松症、多发性骨髓瘤、恶性肿瘤高钙血症、乳腺癌和前列腺癌骨转移.近年来,有关含氮双磷酸盐（帕米磷酸和唑来磷酸）相关性骨坏死的报道日渐增多,其作用机理目前尚不明确.现就双磷酸盐药物致下颌骨坏死的可能作用机制、临床表现、诊断、治疗及预防等相关内容作一综述.     

A case of osteonecrosis of the jaw in a breast cancer patient with bone metastases receiving long-term treatment with bisphosphonates

Bisphosphonates (BPs) are often used for the treatment of several diseases such as osteoporosis, cancer-associated hypercalcemia, and osteolytic bone metastasis. Recently, there have been reports of osteonecrosis of the jaw (ONJ) in cancer patients whose treatment regimens include BPs. In this case report, we describe complications and treatment of ONJ in a breast cancer patient with bone metastases who received long-term treatment with BPs. A 70-year-old woman underwent modified radical mastectomy on her left breast cancer and received oral 5-fluorouracil derivatives for 2 years in another hospital. Eleven years after the surgery, she came to our hospital complaining of spinalgia and was diagnosed with recurrent breast cancer with multiple metastases to the stomach, liver, multiple lymph nodes, and spine. After surgery for spine metastases, she was given a combination therapy of trastuzumab (initial bolus: 170 mg/body, followed by two or more cycles of 85 mg/body) every week, docetaxel (100 mg/body) every 3 weeks, and BPs (90 mg/body) every 4 weeks. About 1 year and 4 months later, she complained of pain in her right maxilla; biopsy revealed ONJ. Medical oncologists need to recognize ONJ as a serious side effect of BP treatment; dentists and oral and maxillofacial surgeons need to thoroughly consult patients regarding the administration of BPs and have them make an informed consent.     

Osteonecrosis of the jaw and bisphophonates in oncology

Bisphosphonates are potent osteoclastic inhibitors that are indicated in the prevention of bone complications. They could also be of interest in the prevention of bone metastases. Several recent international publications have highlighted the onset of osteonecrosis of the jaw (ONJ) in patients treated with bisphosphonates. These osteonecroses manifest in the form of bone exposure, recent tooth mobility, swelling and inflammation and, occasionally, localised pain but they can remain asymptomatic for weeks or even months. The prevalence of these osteonecroses in cancer patients treated with bisphosphonates could range from 1 to 10%. In most cases (60 to 80%), ONJ develops after alveolo-dental surgery (e.g. tooth extraction). Length of exposure to bisphosphonate probably increases the risk. Our recommendations regarding the diagnosis, classification, prevention and treatment of cases of ONJ observed during bisphosphonate administration are based on published studies and our experience. It is obvious that the use of bisphosphonates is undoubtedly beneficial in the treatment of bone complications but the incidence of ONJ during long-term treatments and at high doses warrants preventive measures. These measures are straightforward : bucco-dental repair prior to treatment, good hygiene and regular monitoring during treatment. Current, non-invasive procedures are still permitted. In other cases, the suspension of treatment is indicated until healing is complete. The increase in the incidence of ONJs, serious adverse events, raises the issue regarding duration and administration of bisphosphonate treatment in the management of bone metastases. Studies are currently underway in an attempt to answer this issue.     

Osteonecrosis of the jaw in prostate cancer patients with bone metastases treated with zoledronate: a retrospective analysis

Osteonecrosis of the jaw (ONJ) has recently been reported as a potentially serious complication of prolonged treatment with intravenous bisphosphonates. We studied its frequency in prostate cancer patients receiving intravenous zoledronate. The medical and dental records of 52 consecutive patients with prostate cancer and bone metastases treated at our institute between January 2002 and October 2005 were reviewed. All patients received intravenous zoledronate 4 mg every 3 or 4 weeks and concomitant conventional prostate cancer treatments. We analysed the association of ONJ with the number of administrations of zoledronate and exposure to chemotherapy. At a median follow-up of 7 months (range 1-41) after the initiation of zoledronate, ONJ occurred in six patients (12%, 95% C.I. 5.4-23.0%). All six ONJ cases occurred after the 9^th administration of zoledronate. The median number of zoledronate administrations was 17 (range 9-24) and 8 (range 1-32) for patient developing and not developing ONJ, respectively (p =0.02). Chemotherapy with docetaxel was also associated with a strong, but not statistically significant, trend towards increased risk of ONJ (OR 3.8, 95% C.I. 0.4-35.6, p =0.24). The length of exposure to zoledronate was associated with an increased frequency of ONJ in prostate cancer patients. A possible role of chemotherapy with docetaxel as a cofactor for ONJ merits further evaluation.     

Renal toxicity and osteonecrosis of the jaw in cancer patients treated with bisphosphonates: a long-term retrospective analysis

Background: Bisphosphonates (BPs) are the mainstay of bone-directed therapy for bone metastases from multiple myelomas and a wide range of solid tumours, but some patients experience renal toxicity or osteonecrosis of the jaw (ONJ). Patients and methods: We reviewed data relating to 398 patients treated with intravenous BP for bone metastases, checking their serum creatinine levels throughout the treatment period in order to assess renal function, and seeking any signs and symptoms of ONJ recorded in their medical records. We also analysed other risk factors for renal toxicity and ONJ in patients who developed them. Results: The median treatment period was 14 months (range 1–119); 108 patients received BP for more than 1 year, and 112 for more than 2 years. Sixteen patients (4%) developed renal toxicity after a median of 24 months of BP treatment, eight of them had been treated for more than 2 years. Ten patients (2.5%) were diagnosed as having ONJ after a median of 39 months on BP, only three of them had been treated for less than 2 years. Two patients experienced both ONJ and renal toxicity. Conclusions: The low incidence of ONJ and renal toxicity indicates the safety of BP. However, prevention and early detection are still the “first-line therapy” for decreasing their occurrence further.     

Awareness of breast cancer incidence and risk factors among healthy women.

The efficacy of early breast cancer detection programmes seems to be mainly influenced by the awareness of breast cancer in general among healthy women. This study aimed to provide information about women's understanding of breast cancer incidence and risk of disease. Based on a newly developed questionnaire 2108 healthy women were asked about their knowledge and perceptions in relation to breast cancer incidence, risk factors, risk perception and level of concern. Of these women 78.8% were well aware of breast cancer in general terms. However, there were major aspects such as incidence or risk factors that were poorly understood. Only one-third correctly estimated the incidence of breast cancer; 95% understood breast cancer in the familial history as a risk factor, but only 57% understood the age risk; 37.1% of women perceived hormonal contraceptives and 35.9% hormonal replacement therapy as risk factors of breast cancer. The latter estimation was significantly higher in women above 40 years. Recommendations for the improvement of cancer prevention programmes include targeting understanding of lifetime risk of breast cancer, age as a risk factor, survival from breast cancer or hormonal factors. There is a need to separately address the perceptions of women depending on age, social status and educational levels.