Efeito dos géis de atorvastatina e do polissacarídeo do Agaricus blazei sobre os aspectos morfofuncionais do tecido ósseo de ratas submetidas a osteonecrose de maxilares induzida por ácido zoledrônico

Abstract

Bisphosphonates (PBs) are antiresorptive drugs used on the treatment of severe osteoporosis and bone cancer, because they act reducing osteoclast function leading to apoptosis. Despite its beneficial effects on bone-resorptive diseases. BPs have been associated to important side effects, highlighting bisphosphonate-related osteonecrosis of the jaws (BRONJ). The biological mechanisms underlying BRONJ are yet to clarified. However, it is known that the reduction on osteoblast, osteocyte and blood vessels and inflammation can also play an important role on BRONJ onset. In this context, pharmacological agents that aim to stimulate bone metabolism and simultaneously induce angiogenesis, and modulate the inflammatory process seem to be interesting therapeutic targets to be explored in order to prevent or mitigate BRONJ. Among them, we can highlightAtorvastatin (ATV) and the polysaccharide derived from Agaricus blazei (PAb) due to its bone anabolic, angiogenic, anti-inflammatory antimicrobial and healing properties in different tissues. Thus, the aims of this study were: 1) to perform a systematic review about the topic effect of ATV on alveolar bone in individuals with alveolar inflammatory bone loss; 2) to investigate the antiresoprtive, anti-inflammatory and proangiogenic effects of ATV gel on bone tissue of rats submitted to BRONJ by Zoledronic Acid (ZA); to investigate the effect of PAb gel on bone remodeling in rats submitted to BRONJ induced by ZA. For aim 1, 2 reviewers, using 9 data bank, selected 10 randomized clinical trials about the local effect of ATV gel on alveolar inflammatory bone loss. ATV gel reduced alveolar bone loss and modulated the inflammatory process contributing to bone homeostasis, improving clinical periodontal parameters. Therefore, we can conclude that the use of local ATV protected bone tissue and this type of administration can be useful in order to prevent and treat inflammatory bone loss. For aims 2 and 3, wistar rats were divided in experimental groups: Control (Control) receiving 0.1 mg/kg of 0.9% saline solution (i.p.), 3 x/swk for 9 wk, after tooth extraction on the 8th wk (D49) received placebo gel; ZA receiving 0.1 mg/kg of ZA (i.p.), 3 x/wk for 9wk., after tooth extraction on the 8th wk received placebo gel; ATV gel received 0.1 mg/kg AZ (i.p.), 3 x/swk for 9 wk, after tooth extraction on the 8th wk (D49) received 1.2% ATV gel (Aim 2); PAb gel receiving 0.1 mg/kg of ZA (i.p.), 3 x/wk for 9wk., after tooth extraction on the 8th wk received 1.0% PAb gel (Aim 3). On the 8th week all animals were submitted to the extraction of the 1st upper left molar and the gels were administered, in a single time, inside the dental alveolus, according to the experimental group. On the 3rd wk after exodontia (D77), all animals were euthanized, and maxilla collected for macroscopic, histological, radiographic, biomechanical and molecular analysis. Blood samples were collected for hematological, and biochemical dosages. Liver and kidneys were collected as well. ATV or PAb gels reversed the findings seen in the group of animals submitted to BRONJ. Both gels stimulated bone remodeling, with increase on the number and function of osteoblasts. It was observed an increase on type I collagen in the animals treated with ATV or PAb gels compared to ZA group, which was associated to improvement on alveolar bone strength and resistance. ATV gel modulated inflammation and increased the number of blood vessels on alveolar bone. PAb gel

stimulated bone remodeling through activation Wnt signaling. None systemic alteration was observed in either kidneys or liver after ATV gel treatment. In this way, we can conclude that the topical treatment with ATV or PAb gels mitigated BRONJ and may be an useful pharmacological tool for the treatment of this condition.