Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases

Saad, Fred; Brown, Janet; Poznak, Catherine Van; Ibrahim, Toni; Stemmer, Salomon M.; Stopeck, Alison; Diel, Ingo J.; Takahashi, Shunji; Shore, Neal D.; Henry, David H.; Barrios, Carlos H.; Facon, Thierry; Senecal, Frank M.; Fizazi, Karim; Zhou, Lifen; Daniels, A.; Carriere, Phillipe; Dansey, Roger

doi:10.1093/annonc/mdr435

Cited by 680 publications

(578 citation statements)

References 30 publications

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“…The approach to MRONJ should be multidisciplinary and include an appropriated dental evaluation before initiating the antiresorptive or antiangiogenic to reduce local risk factors (5,(14)(15)(16)(17)(18). Whenever MRONJ cannot be avoided, local treatment consists in eliminating the pain and control local infection.…”

Section: Mronj Was First Reported In 2003 But Its Pathophysiologymentioning

confidence: 99%

Surgery Combined with LPRF in Denosumab Osteonecrosis of the Jaw: Case Report

et al. 2016

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This paper describes two cases in which the use of leucocyte-rich and platelet-rich fibrin (LPRF) combined with bone resection did not result in complete tissue response in the treatment of medication-related osteonecrosis of the jaw (MRONJ). It has been recently described in patients receiving subcutaneous administration of RANK-inhibitors, such as Denosumab, and anti-angiogenic drugs, such as Bevacizumab, as observed in our cases. Due to promising results in recent studies, more patients will receive these medications in order to avoid skeletal complications due to metastatic bone disease and, therefore, this scenario has a potential to become a comparable challenge to the bisphosphonateinduced jaw necrosis in the area of Oral and Maxillofacial Surgery. No convincing surgical technique has been described to overcome the non-healing mucosal lesions with exposed bone due to RANK-inhibitor therapy. Based on the findings in the literature and in both cases described herein can be concluded that the use of LPRF should be considered in the treatment of patients with DRONJ. S u r g e r y C o m b i n e d w i t h L P R F i n D e n o s u m a b O s t e o n e c r o s i s o f t h e J a w : C a s e R e p o r t

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Section: Mronj Was First Reported In 2003 But Its Pathophysiologymentioning

confidence: 99%

Surgery Combined with LPRF in Denosumab Osteonecrosis of the Jaw: Case Report

et al. 2016

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“…Such an increase in ONJ frequency highlights the need for longer patients' monitoring and the adoption of nonparametric actuarial estimation (Kaplan-Meier), as done in other studies [10] the integrated analysis of the results of three pivotal trials of blinded comparison between denosumab and zoledronic acid: they also reported the number of Bpotential ONJ^cases that were initially registered as spontaneously reported by investigators or on the base of 36 MedDRA (Medical Dictionary for Regulatory Activities) adverse oral event terms. BPotential ONJ^cases, defined by the presence of clinical sign and symptoms suggestive of ONJ, were three times higher than the finally Badjudicated ONJ^cases: 276/5723 (4.8 %) versus 89/5723 (1.5 %).…”

Section: To the Editormentioning

confidence: 99%

“…BPotential ONJ^cases, defined by the presence of clinical sign and symptoms suggestive of ONJ, were three times higher than the finally Badjudicated ONJ^cases: 276/5723 (4.8 %) versus 89/5723 (1.5 %). Of importance, such data were recorded after a relatively short observation time, being the median (Q1, Q3) time on study 12.1 (5.4, 19.4) months for patients in the ZA group and 12.6 (5.6, 19.4) months for patients in the denosumab group [10]. We believe that it would be of great value if the authors of the extension study [1] could report the number of Bpotential ONJ^cases (defined as above) observed in the breast and prostate cancer population of the extension study, and compare them with those of the blinded study, and those among patients who declined shift to denosumab, if available.…”

Section: To the Editormentioning

confidence: 99%

Definition and estimation of osteonecrosis of jaw (ONJ), and optimal duration of antiresorptive treatment in bone metastatic cancer patients: supplementary data from the denosumab extension study?

Fusco

Bedogni

Addeo

et al. 2016

Support Care Cancer

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To the Editor,In their recent article, Stopeck et al. [1] concluded that denosumab confirms its known safety profile even after longterm exposure, or after switching to it from zoledronic acid, and that osteonecrosis of jaws (ONJ) rates increased with increasing exposure to antiresorptives, consistent with previous reports. This is based on the open label extension phase of two phase 3 studies in patients with breast and prostate cancer with bone metastases who were randomized to receive denosumab or zoledronic acid (ZA) [2,3]. The patients were offered open-label denosumab for up to an additional 2 years after the results of the primary analysis, favorable for denosumab on several aspects. Patients initially randomized to denosumab (denosumab/ denosumab group) continued to receive denosumab at 120 mg Q4W whereas patients on ZA were switched to denosumab in the open-label phase (ZA/denosumab group) at 120 mg Q4W starting 4 weeks from their last ZA dose. Patients who declined further therapy in the open-label extension phase, or who did not complete the blinded treatment phase, continued follow-up for survival every 12 weeks (Q12W) for up to 2 years after their last dose.We collected data from the text and the tables of the paper published by Stopeck et al. [1] and summarized them in a new table (Table 1).Although authors' conclusions are quite reassuring both in terms of denosumab safety and efficacy, it is noteworthy that the median exposure of patients to denosumab in the extension phase study is lower than expected, even in the presence of a longer range. The final median exposure of the 318 denosumab/denosumab breast cancer patients is 19.1 months (range 0.1-59.8), not much longer than that registered for the whole cohort of the 1019 breast cancer patient population enrolled in the blinded phase, that was 17.6 months (range 0-23.7). As far as prostate cancer patients are concerned, the median denosumab exposure was 12.0 months (range 0.1-67.2) for the 147 denosumab/denosumab patients from the extension study versus 12.0 months (range 0.1-23.3) for the 942 patients enrolled in the original randomized trial. We could not work out from the paper the median denosumab exposure for 318 breast and 147 prostate cancer patients of the extension study denosumab/denosumab population in the previous blinded phase. This appears to us a weakness of the article.Interestingly, the frequency of ONJ cases in the open label extension study appears substantially higher than what is found in the initial blinded phase (ONJ frequency ranging from 1 to 2 %) [2, 3] despite median denosumab exposure was not significantly longer in the former. The crude ONJ figures increased both in denosumab/denosumab groups and in ZA/denosumab populations: ONJ cases were respectively 20/318 (6.3 %) in breast patients and 12/147 (8.2 %) in prostate patients in the denosumab/denosumab group, whereas they were 18/334 (5.4 %) breast patients and 7/118 (5.9 %) prostate patients in the ZA/denosumab group.Such an increase in ONJ frequency highlights the ne...

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“…Longer duration of therapy, higher cumulative doses, treatment with more potent bisphosphonates (zoledronic acid and pamidronate), history of recent alveolar trauma and inflammatory dental disease are known risk factors for ONJ (Hoff et al, 2008;Hoff et al, 2011). Glucocorticoid treatment or antiangiogenic therapy may also contribute to ONJ development (Saad et al, 2012). Bisphosphonates accumulate in the bone and effect of denosumab on bone become reversible after several months.…”

Section: Safetymentioning

confidence: 99%

Medical Treatment of Breast Cancer Bone Metastasis: From Bisphosphonates to Targeted Drugs

Erdoğan

Çiçin²

2014

Asian Pacific Journal of Cancer Prevention

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Breast cancer bone metastasis causing severe morbidity is commonly encountered in daily clinical practice. It causes pain, pathologic fractures, spinal cord and other nerve compression syndromes and life threatening hypercalcemia. Breast cancer metastasizes to bone through complicated steps in which numerous molecules play roles. Metastatic cells disrupt normal bone turnover and create a vicious cycle to which treatment efforts should be directed. Bisphosphonates have been used safely for more than two decades. As a group they delay time to first skeletal related event and reduce pain, but do not prevent development of bone metastasis in patients with no bone metastasis, and also do not prolong survival. The receptor activator for nuclear factor kB ligand inhibitor denosumab delays time to first skeletal related event and reduces the skeletal morbidity rate. Radionuclides are another treatment option for bone pain. New targeted therapies and radionuclides are still under investigation. In this review we will focus on mechanisms of bone metastasis and its medical treatment in breast cancer patients.

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Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases

Cited by 680 publications

References 30 publications

Surgery Combined with LPRF in Denosumab Osteonecrosis of the Jaw: Case Report

Surgery Combined with LPRF in Denosumab Osteonecrosis of the Jaw: Case Report

Definition and estimation of osteonecrosis of jaw (ONJ), and optimal duration of antiresorptive treatment in bone metastatic cancer patients: supplementary data from the denosumab extension study?

Medical Treatment of Breast Cancer Bone Metastasis: From Bisphosphonates to Targeted Drugs

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