Osteonecrosis of the jaw under bisphosphonate and antiangiogenic therapies: cumulative toxicity profile?Bisphosphonates are standard treatment of patients with bone metastases but are associated with the serious complication of osteonecrosis of the jaw (ONJ), which is characterized by intraoral lesions exposing necrotic bone [1]. The estimated prevalence of i.v. bisphosphonate-associated ONJ in cancer patients is as high as 6%-10% [1]. In a retrospective analysis, ONJ occurred in 2% of patients treated with bevacizumab and bisphosphonates compared with 1.1% of patients receiving bisphosphonates alone [2]. However, no causal role of bevacizumab has been identified since no patient receiving bevacizumab alone had ONJ [2]. We read with great interest the first case report of ONJ related to bevacizumab [3]. Given that the mechanism of action of bisphosphonates may be attributable in part to an antiangiogenic effect [4,5], an additive toxic effect of antiangiogenic drugs in patients letters to the editor

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Doxorubicin (Doxo) is a widely used antineoplastic drug with limited clinical application due to its deleterious dose-related side effects. We investigated whether nicotinamide mononucleotide (NMN) could protect against Doxo-induced cardiotoxicity and physical dysfunction in vivo. To assess the short- and long-term toxicity, two Doxo regimens were tested, acute and chronic. In the acute study, C57BL6/J (B6) mice were injected intraperitoneally (i.p.) once with Doxo (20 mg/kg) and NMN (180 mg/kg/day, i.p.) was administered daily for five days before and after the Doxo injection. In the chronic study, B6 mice received a cumulative dose of 20 mg/kg Doxo administered in fractionated doses for five days. NMN (500 mg/kg/day) was supplied in the mice’s drinking water beginning five days before the first injection of Doxo and continuing for 60 days after. We found that NMN significantly increased tissue levels of NAD+ and its metabolites and improved survival and bodyweight loss in both experimental models. In addition, NMN protected against Doxo-induced cardiotoxicity and loss of physical function in acute and chronic studies, respectively. In the heart, NMN prevented Doxo-induced transcriptomic changes related to mitochondrial function, apoptosis, oxidative stress, inflammation and p53, and promyelocytic leukemia nuclear body pathways. Overall, our results suggest that NMN could prevent Doxo-induced toxicity in heart and skeletal muscle.

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