Association of Osteonecrosis of the Jaw With Zoledronic Acid Treatment for Bone Metastases in Patients With Cancer

Poznak, Catherine Van; Unger, Joseph M.; Darke, Amy K.; Moinpour, Carol M.; Bagramian, Robert A.; Schubert, Mark M.; Hansen, Lisa; Floyd, Justin D.; Dakhil, Shaker R.; Lew, Danika; Wade, James L.; Fisch, Michael J.; Henry, NL; Hershman, Dawn L.; Gralow, Julie R.

doi:10.1001/jamaoncol.2020.6353

Cited by 46 publications

(28 citation statements)

References 22 publications

(33 reference statements)

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“…Our results are consistent with the earlier findings regarding the risk of ONJ in patients treated with denosumab or zoledronic acid 3‐5,21‐23 . In phase 3 trials among 5723 patients with bone metastases from solid tumors, the ONJ risk was 1.8% with denosumab and 1.3% with zoledronic acid treatment over up to 40 months of follow‐up 3‐5 .…”

Section: Discussionsupporting

confidence: 91%

“…In an observational cohort study in Belgium with a design similar to our study but without expert ONJ adjudication, the 5‐year incidence proportion of ONJ was 10.0% over a median treatment duration of 18 months among denosumab initiators (51% breast cancer), 6.7% over a median treatment duration of 19 months among zoledronic acid initiators (64% breast cancer), and 15.5% over a median cumulative sequential exposure of 36 months among switchers from zoledronic acid to denosumab (82% breast cancer) 24 . In a cohort study in the United States, the 3‐year cumulative incidence of ONJ was 2.8% for patients with cancer on zoledronic acid and 3.2% among patients with cancer on denosumab 23 . It has been hypothesized that switching from bisphosphonates to denosumab, in addition to being a marker of treatment duration, is itself a risk factor for ONJ 25,26 .…”

Section: Discussionmentioning

confidence: 99%

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Osteonecrosis of the jaw among patients with cancer treated with denosumab or zoledronic acid: Results of a regulator‐mandated cohort postauthorization safety study in Denmark, Norway, and Sweden

Ehrenstein

Heide-Jørgensen

Schiødt

et al. 2021

Cancer

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BACKGROUND Osteonecrosis of the jaw (ONJ) is an adverse effect of antiresorptive treatment. This study estimated incidence proportions and incidence rates of ONJ in cancer patients with bone metastases from solid tumors treated for the prevention of skeletal‐related events in routine clinical practice. METHODS This cohort study in Denmark, Norway, and Sweden in 2011‐2018 included 3 treatment cohorts: a denosumab inception cohort (DEIC), a zoledronic acid inception cohort (ZAIC), and a denosumab‐switch cohort (DESC). The authors estimated 1‐ to 5‐year incidence proportions and incidence rates of ONJ overall, by cancer site (breast, prostate, or other solid tumor), and by country. ONJ diagnoses were confirmed by adjudication. RESULTS There were 1340 patients in the DEIC, 1352 in the ZAIC, and 408 in the DESC. The median ages of the 3 cohorts were 70, 69, and 70 years, respectively; the proportions of men were 72.6%, 53.8%, and 48.3%, respectively; and the median follow‐up was 19.8, 12.9, and 13.3 months, respectively. The 5‐year incidence proportions of ONJ were 5.7% (95% confidence interval [CI], 4.4%‐7.3%) in the DEIC, 1.4% (95% CI, 0.8%‐2.3%) in the ZAIC, and 6.6% (95% CI, 4.2%‐10.0%) in the DESC. The corresponding ONJ incidence rates per 100 person‐years were 3.0 (95% CI, 2.3‐3.7), 1.0 (95% CI, 0.6‐1.5), and 4.3 (95% CI, 2.8‐6.3). Incidence proportions and incidence rates were highest in patients with prostate cancer and in Denmark. CONCLUSIONS This study provides estimates of the risk of medically confirmed ONJ among patients initiating denosumab or zoledronic acid in routine clinical practice in 3 Scandinavian countries. The results varied by cancer site and by country. LAY SUMMARY Denosumab and zoledronic acid reduce the risk of bone fractures, pain, and surgery in patients with advanced cancers involving bone. Osteonecrosis of the jaw (ONJ)—death of a jawbone—is a known side effect of treatment with denosumab or zoledronic acid. The authors examined almost 2900 denosumab‐ or zoledronic acid–treated patients with cancer in Denmark, Norway, and Sweden. Over the course of 5 years, ONJ developed in 5.7% of the patients whose initial treatment was denosumab, in 1.4% of the patients whose initial treatment was zoledronic acid, and in 6.6% of the patients who switched from zoledronic acid to denosumab.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Osteonecrosis of the jaw among patients with cancer treated with denosumab or zoledronic acid: Results of a regulator‐mandated cohort postauthorization safety study in Denmark, Norway, and Sweden

Ehrenstein

Heide-Jørgensen

Schiødt

et al. 2021

Cancer

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“…The systematic review by Ottesen et al, 2020, showed that most of the clinical cases of MRONJ described in the literature occurred after tooth extraction, that is, in about 50-70% of cases [14][15][16]. However, the infectious process leading to the extraction of teeth is primary, just like the infection that develops around the implants.…”

Section: Discussionmentioning

confidence: 99%

Assessment of Quality of Life in Patients with Medication-Related Osteonecrosis of the Jaw Following Reconstructive and Restorative Surgery

et al. 2021

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Recently, numerous articles have been published describing atypical lesions of the jaw bones related to treatment with medications based on phosphorus or analogs of its compounds, particularly bisphosphonates. Goal: To conduct a comparative analysis of the quality of life after radical surgery of the jaw in patients with medication-related osteonecrosis. A total of 82 patients were interviewed, of which 39 (47.6%) patients were in the control group (conservative treatment) and 43 (52.4%) patients in the main group had radical surgical treatment. The mean age of patients in both groups was 66.8 ± 10.03 years. Treatment of patients in the control group in terms of conventional conservative protocol included the local application of 0.05% chlorhexidine solution 1–2 times a day, antibacterial therapy (clindamycin—150 mg 4 times daily for 7 days) and NSAIDs (nimesulide). Patients in the main group (n = 43) underwent segmental resection of the jaw. Thirty days and then 6 months after the treatment, all patients were asked to assess the intensity of pain using a numerical scale, where 0 = no pain, 5 = moderate pain and 10 = the most severe pain imaginable, and to fill in the SF-36 Quality of Life Questionnaire. Results: An analysis of the results obtained with the Numeric Pain Rating Scale demonstrated that the mean pain intensity before treatment was 8.9 points in the control group, and 9.7 in the main group. These values were indicative of “unbearable pain.” After treatment (30 days), the pain score in the control group decreased and amounted to 4.1, which is evidence of the persistence of “moderate pain” in patients. In patients who underwent segmental jaw resection, the mean pain intensity was 0.5. There was no relationship with gender, but there was a direct relationship between the intensity of the pain and the stage of the process (CI = 95%). The SF-36 quality of life questionnaire showed that in the control group, who were treated conservatively, bodily pain (BoP) decreased from a score of 91.2 to 34.3, and the mental health score increased from 34.2 before treatment to 36.3 after treatment, which indicates the persistence of discomfort. The remaining parameters improved after treatment, but no complete recovery was achieved. Before radical surgery, the main group of patients also had a high level of bodily pain (95.2), but after surgery this decreased to 12.4. The remaining parameters also showed a significant difference before and after radical surgery, indicating a positive trend. Radical surgery allows us to improve the quality of life of patients, thereby confirming that surgical volume is a secondary aspect if there is no relapse after the treatment.

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“…However, emerging data on the development of MRONJ raise new concerns about the duration and cumulative dose of N-BP administration. The cumulative incidence of developing MRONJ among patients receiving intravenous N-BPs increased from 0.5–0.8% at 1 year to 1.3–4.3% at 3 years without a plateau after 2–3 years as reported for patients receiving an alternative antiresorptive drug denosumab [ 1 , 3 ]. The increasingly accumulated N-BPs in the long-term use of N-BPs may be expected in the bone of patients, and the high level released during bone remodelling is considered to increase the risk of developing MRONJ [ 4 – 6 ].…”

Section: Introductionmentioning

confidence: 99%

Geranylgeraniol prevents zoledronic acid-mediated reduction of viable mesenchymal stem cells via induction of Rho-dependent YAP activation

2021

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Long-term use of zoledronic acid (ZA) increases the risk of medication-related osteonecrosis of the jaw (MRONJ). This may be attributed to ZA-mediated reduction of viable mesenchymal stem cells (MSCs). ZA inhibits protein geranylgeranylation, thus suppressing cell viability and proliferation. Geranylgeraniol (GGOH), which is a naturally found intermediate compound in the mevalonate pathway, has positive effects against ZA. However, precise mechanisms by which GGOH may help preserve stem cell viability against ZA are not fully understood. The objective of this study was to investigate the cytoprotective mechanisms of GGOH against ZA. The results showed that while ZA dramatically decreased the number of viable MSCs, GGOH prevented this negative effect. GGOH-rescued ZA-exposed MSCs formed mineralization comparable to that produced by normal MSCs. Mechanistically, GGOH preserved the number of viable MSCs by its reversal of ZA-mediated Ki67 + MSC number reduction, cell cycle arrest and apoptosis. Moreover, GGOH prevented ZA-suppressed RhoA activity and YAP activation. The results also established the involvement of Rho-dependent YAP and YAP-mediated CDK6 in the cytoprotective ability of GGOH against ZA. In conclusion, GGOH preserves a pool of viable MSCs with osteogenic potency against ZA by rescuing the activity of Rho-dependent YAP activation, suggesting GGOH as a promising agent and YAP as a potential therapeutic target for MRONJ.

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Association of Osteonecrosis of the Jaw With Zoledronic Acid Treatment for Bone Metastases in Patients With Cancer

Cited by 46 publications

References 22 publications

Osteonecrosis of the jaw among patients with cancer treated with denosumab or zoledronic acid: Results of a regulator‐mandated cohort postauthorization safety study in Denmark, Norway, and Sweden

Osteonecrosis of the jaw among patients with cancer treated with denosumab or zoledronic acid: Results of a regulator‐mandated cohort postauthorization safety study in Denmark, Norway, and Sweden

Assessment of Quality of Life in Patients with Medication-Related Osteonecrosis of the Jaw Following Reconstructive and Restorative Surgery

Geranylgeraniol prevents zoledronic acid-mediated reduction of viable mesenchymal stem cells via induction of Rho-dependent YAP activation

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