Abstract
ObjectivesTo determine the extent that zoledronate (ZOL) dose and duration is associated with bisphosphonate‐related osteonecrosis of the jaw (BRONJ) prevalence in rice rats with generalized periodontitis (PD), characterize structural and tissue‐level features of BRONJ‐like lesions in this model, and examine the specific anti‐resorptive role of ZOL in BRONJ.Materials and MethodsRice rats (n = 228) consumed high sucrose‐casein diet to enhance generalized PD. Groups of rats received 0, 8, 20, 50 or 125 µg/kg IV ZOL/4 weeks encompassing osteoporosis and oncology ZOL doses. Rats from each dose group (n = 9–16) were necropsied after 12, 18, 24 and 30 weeks of treatment. BRONJ‐like lesion prevalence and tissue‐level features were assessed grossly, histopathologically and by MicroCT. ZOL bone turnover effects were assessed by femoral peripheral quantitative computed tomography, serum bone turnover marker ELISAs and osteoclast immunolabelling.ResultsPrevalence of BRONJ‐like lesions was significantly associated with (a) ZOL treatment duration, but plateaued at the lowest oncologic dose, and (b) there was a similar dose‐related plateau in the systemic anti‐resorptive effect of ZOL. ZOL and BRONJ‐like lesions also altered the structural and tissue‐level features of the jaw.ConclusionThe relationship between BRONJ‐like lesion prevalence and ZOL dose and duration varies depending on the co‐ or pre‐existing oral risk factor. At clinically relevant doses of ZOL, BRONJ‐like lesions are associated with anti‐resorptive activity.
Highlights
Medication‐related osteonecrosis of the jaw (MRONJ) is a potentially severe adverse event characterized by persistent exposure of necrotic bone in the jaw (Ruggiero et al, 2014) in patients treated with potent anti‐resorptives [e.g., nitrogen‐containing bisphosphonates, N‐BPs (Marx, 2003; Ruggiero et al, 2014), and receptor activator of NFκB ligand antibodies (Stopeck et al, 2010; Van den Wyngaert, Wouters, Huizing, & Vermorken, 2011)]
This study demonstrates a duration‐dependent increase in the prevalence of bisphosphonate‐related osteonecrosis of the jaw (BRONJ) with oncologic ZOL in rice rats with progressive generalized PD
BRONJ prevalence plateaued at a dose only 2.5‐fold higher than prevalence with the osteoporosis dose and was consistent with a similar plateau in the anti‐resorptive effects of ZOL
Summary
Medication‐related osteonecrosis of the jaw (MRONJ) is a potentially severe adverse event characterized by persistent exposure of necrotic bone in the jaw (Ruggiero et al, 2014) in patients treated with potent anti‐resorptives (pARs) [e.g., nitrogen‐containing bisphosphonates, N‐BPs (Marx, 2003; Ruggiero et al, 2014), and receptor activator of NFκB ligand antibodies (Stopeck et al, 2010; Van den Wyngaert, Wouters, Huizing, & Vermorken, 2011)]. Local factors in the oral cavity, despite being absent from the formal definition of MRONJ, increase risk and play a crucial role in the disease process (Aghaloo, Hazboun, & Tetradis, 2015; Aljohani et al, 2017; Carlson & Schlott, 2014; Eleutherakis‐Papaiakovou & Bamias, 2017; Filleul, Crompot, & Saussez, 2010; Hamadeh, Ngwa, & Gong, 2015; Khan et al, 2017; Marx, 2003; Otto et al, 2012; Voss et al, 2017; Yoneda et al, 2017). Cases in which MRONJ arises without a recent dentoalveolar surgery may be
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