The effect of melatonin on prevention of bisphosphonate-related osteonecrosis of the jaw: an animal study in rats

Abstract

Objectives: Melatonin induces human stem cells, converts pre-osteoblasts to mature osteoblasts, and reduces the duration of this transition. However, melatonin itself prevents activation of osteoclasts. Here, we evaluate the role of melatonin in prevention of bisphosphonate-related osteonecrosis of the jaw. Materials and Methods: In this experimental-interventional study, 30 rats were evaluated in 3 groups. The first and second groups received saline and zoledronic acid, respectively, for 4 weeks and the third group received 4 weeks of zoledronic acid and 3 weeks of melatonin simultaneously. Firstright-maxillary-molar extraction was performed for all animals, which were sacrificed after 4 weeks of recovery. The extraction sockets were examined histologically for the presence of osteonecrosis, number of osteoclasts and fibroblasts, severity of inflammation, and vascularization. Data were analyzed by chi-square, one-way ANOVA, Tukey, Kruskal-Wallis and Fisher's exact statistical tests (α=0.05). Results: Osteonecrosis was observed in 20%, 90%, and 70% of the first, second and third groups, respectively (P=0.008). The lowest number of osteoclasts and fibroblasts was seen in the third group. Conclusion: Melatonin may effectively prevent some undesirable side effects of bisphosphonates. However, further studies are required to confirm the results of this study.

Establishment and assessment of rodent models of medication-related osteonecrosis of the jaw (MRONJ)

“…Regarding species selection, approximately 60% of relevant studies chose rats rather than mice for research, usually 8–12 weeks old and female 44 – 48 . Rats were selected due to their low cost, rapid and easy reproduction, and simple maintenance conditions 49 . They have a larger size and can live longer in such a long experimental period compared with mice.…”

“… Histopathological assessments Healing conditions 59 , 60 , 63 , 98 Histological sections show the soft tissue healing with the distance between the edges of the epithelia, and bone defects with the length of the necrotic bone exposed towards the oral cavity. Necrotic bone 49 , 57 – 59 , 64 , 69 , 72 , 96 , 100 The presence of necrotic bone represents the occurrence of MRONJ. The definition of necrotic bone depends on the number of confluent empty or karyolytic osteocytic lacunae.…”

“… Empty bone lacunae 30 , 45 , 95 , 96 , 98 The proportion or the number of empty bone lacunae in a certain area indicates the degree of osteocyte loss, which present the bone necrosis. TRAP + osteoclast 44 , 49 , 57 , 58 , 64 , 67 , 69 , 72 , 93 , 95 – 101 The TRAP + osteoclasts present the bone resorption, commonly used indicators including numbers of osteoclast per area or per bone line. Osteoblast 30 , 44 , 49 , 64 , 67 , 93 , 97 Generally identified by hematoxylin-eosin staining or marked by alkaline phosphatase (ALP), bone morphogenetic protein-2 (BMP-2), or receptor activators of NF-κB ligand (RANKL), commonly used indicators including numbers of osteoclast per area or per bone line.…”

“… TRAP + osteoclast 44 , 49 , 57 , 58 , 64 , 67 , 69 , 72 , 93 , 95 – 101 The TRAP + osteoclasts present the bone resorption, commonly used indicators including numbers of osteoclast per area or per bone line. Osteoblast 30 , 44 , 49 , 64 , 67 , 93 , 97 Generally identified by hematoxylin-eosin staining or marked by alkaline phosphatase (ALP), bone morphogenetic protein-2 (BMP-2), or receptor activators of NF-κB ligand (RANKL), commonly used indicators including numbers of osteoclast per area or per bone line. Blood vessels 65 , 67 , 69 The extent of angiogenic inhibition is assessed by the density of blood vessels generally marked by CD31.…”

“… Blood vessels 65 , 67 , 69 The extent of angiogenic inhibition is assessed by the density of blood vessels generally marked by CD31. Inflammation 49 , 67 , 99 The extent of inflammation is assessed by the number of polymorphonuclear cells under fixed area, as well as the infiltration and bone sequestra. Serological assessments VEGF 67 , 98 , 103 Serum VEGF presents the angiogenic ability of MRONJ.…”