Abstract
The goal of this investigation was to identify potential risk factors to predict the onset of medication-related osteonecrosis of the jaw (MRONJ). Through the identification of the multiple variables positively associated to MRONJ, we aim to write a paradigm for integrated MRONJ risk assessment built on the combined analysis of systemic and local risk factors. The characteristics of a cohort of cancer patients treated with zoledronic acid and/or denosumab were investigated; beyond the set of proven risk factors a new potential one, the intake of new molecules for cancer therapy, was addressed. Registered data were included in univariate and multivariate logistic regression analysis in order to individuate significant independent predictors of MRONJ; a propensity score-matching method was performed adjusting by age and sex. Univariate logistic regression analysis showed a significant effect of the parameters number of doses of zoledronic acid and/or denosumab (OR = 1.03; 95% CI = 1.01–1.05; p = 0.008) and chemotherapy (OR = 0.35; 95% CI = 0.17–0.71; p = 0.008). The multiple logistic regression model showed that breast, multiple myeloma, and prostate cancer involved a significantly higher risk compared to lung cancer; a significant effect of the combined variables number of doses of zoledronic acid and/or denosumab (OR = 1.03; 95% CI = 1.01–1.06); p-value = 0.03) and exposure to novel molecule treatment (OR = 34.74; 95% CI = 1.39–868.11; p-value = 0.03) was observed. The results suggest that a risk assessment paradigm is needed for personalized prevention strategies in the light of patient-centered care.
Highlights
Medication-related osteonecrosis of the jaws (MRONJ) can be defined as “a drugrelated adverse reaction, characterized by progressive bone destruction and necrosis of both the mandible and the maxilla, in patients taking aminobisphosphonates or other drugs, with no other predisposing conditions” [1].In the setting of cancer, the antiresorptive medications zoledronic acid and denosumab prescribed to prevent skeletal-related events associated with solid tumor-related bone metastases and with lytic lesions associated to multiple myeloma have been associated to MRONJ, in view of their inhibitory effects on osteoclastic bone resorption and remodeling
We found a significant effect of the number of administered doses of zoledronic acid/denosumab (OR = 1.03; 95% CI = 1.01; 1.05; p = 0.008) and chemotherapy (OR = 0.35; 95% CI = 0.17–0.71; p = 0.008) on MRONJ onset (Table 3)
Examining the results via a multiple logistic regression model, we found that all examined cancer types involved a significantly higher risk of MRONJ onset compared to the lung cancer type
Summary
In the setting of cancer, the antiresorptive medications zoledronic acid and denosumab prescribed to prevent skeletal-related events associated with solid tumor-related bone metastases and with lytic lesions associated to multiple myeloma have been associated to MRONJ, in view of their inhibitory effects on osteoclastic bone resorption and remodeling. Bisphosphonates bind to the bone mineral and determine osteoclast apoptosis, preventing the inhibitory effect of mature osteoclasts; in particular, aminobisphosphonates inhibit the mevalonate pathway enzyme farnesyl diphosphate (FPP) synthase in osteoclasts (Ocs), which leads to reduced production of specific intracellular proteins necessary for osteoclast function and survival, resulting in cell apoptosis. Denosumab precludes the binding of RANK-L to its receptor RANK on the surface of osteoclast OC precursors essential for the proliferation, differentiation, and survival of OC, since it is RANKL that initiates a complex signaling pathway which modulates intracellular calcium oscillation and turns on osteoclastogenesis [4,5,6]
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