Switching from zoledronic acid to denosumab increases the risk for developing medication-related osteonecrosis of the jaw in patients with bone metastases

Abstract

Purpose Switch from zoledronic acid (ZA) to denosumab may increase the risk of medication-related osteonecrosis of the jaw (MRONJ) owing to the additive effect of denosumab on the jawbone and residual ZA activities. We evaluated the risk of developing MRONJ in patients who received ZA, denosumab, or ZA-to-denosumab for the treatment of bone metastases. Methods The medical charts of patients with cancer who received denosumab or ZA for bone metastases were retrospectively reviewed. Patients who did not undergo a dental examination at baseline were excluded. Primary endpoint was the evaluation of the risk of developing MRONJ in the ZA-to-denosumab group. Secondary endpoints were probability of MRONJ and the relationship between risk factors and the time to the development of MRONJ. Results Among the 795 patients included in this study, 65 (8.2%) developed MRONJ. The incidence of MRONJ was significantly higher in the ZA-to-denosumab group than in the ZA group [7/43 (16.3%) vs. 19/350 (5.4%), p = 0.007]. Multivariate Cox proportional hazards regression analysis revealed that denosumab treatment [hazard ratio (HR), 2.41; 95% confidence interval (CI), 1.37–4.39; p = 0.002], ZA-to-denosumab treatment (HR, 4.36; 95% CI, 1.63–10.54, p = 0.005), tooth extraction after starting ZA or denosumab (HR, 4.86; 95% CI, 2.75–8.36; p < 0.001), and concomitant use of antiangiogenic agents (HR, 1.78; 95% CI, 1.06–2.96; p = 0.030) were significant risk factors for MRONJ. Conclusion Our results suggest that switching from ZA to denosumab significantly increases the risk for developing MRONJ in patients with bone metastases.

Zoledronic acid inhibits osteoclastogenesis and bone resorptive function by suppressing RANKL‑mediated NF‑κB and JNK and their downstream signalling pathways

“…The data suggested that BRONJ caused by denosumab resolves faster than that caused by ZOL. It was also reported that switching from ZOL to denosumab markedly increased the risk of developing BRONJ in patients with bone metastases ( 60 ). That is likely due to ZOL having high affinity for bone hydroxyapatite, thus leading to prolonged drug action and excessive toxic effects.…”

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

“…Switching from BPs to denosumab has been hypothesized to raise the risk of ONJ development. ( 18‐23 ) Nine of the 12 patients who developed ONJ under denosumab were previously treated with BPs for a mean duration of 6.7 years. Because of the long‐term effects of BPs and their incorporation into bone mineral, it can be assumed that these drugs increase the risk of ONJ development during subsequent therapy with denosumab, at least in patients with only short breaks between treatment sequences.…”

Management von medikamentenassoziierten Kiefernekrosen – Ergebnisse einer Literaturanalyse neuester Studien im Vergleich zu bewährten Strategien

“…Die Literatursuche zur Pathogenese der MRONJ ergab 186 Treffer, von denen schließlich 8 Arbeiten berücksichtigt wurden [ 10 , 12 , 16 , 20 , 31 , 32 , 43 , 46 ]. Die bereits formulierte Pathogenesetheorie, dass chronische Entzündungen ursächlich mit der Entstehung von MRONJ verbunden sind, wird in allen Studien bestätigt.…”