Preventive effect of fluvastatin on the development of medication-related osteonecrosis of the jaw

Abstract

Medication-related osteonecrosis of the jaw (MRONJ) occurs in patients undergoing oral surgery while medicated with bisphosphonate, denosumab or anti-angiogenic agents. We employed a MRONJ-like rat model to investigate whether injecting fluvastatin at extraction sites prevents MRONJ-like lesion. A MRONJ-like model was created by treating rats with zoledronate and dexamethasone, extracting teeth, and immediately injecting fluvastatin at the extraction site. The experimental group comprised three subgroups treated with low (0.1 mg/kg; FS-L), medium (1.0 mg/kg; FS-M) and high concentrations (10 mg/kg; FS-H) of fluvastatin. Necrotic bone exposure was significantly lower in the FS-M (p = 0.028) and FS-H (p = 0.041) groups than in the MRONJ group. The distance between the edges of the epithelial surfaces was significantly shorter in the FS-M (p = 0.042) and FS-H (p = 0.041) groups. The area of necrotic bone and the necrotic bone ratio were significantly smaller in the FS-H group (p = 0.041 and p = 0.042 respectively). Bone volume fraction calculated on μ-CT images was significantly larger in the FS-H group than in the MRONJ group (p = 0.021). Our findings suggest that a single local injection of fluvastatin following tooth extraction can potentially reduce the chance of developing MRONJ-like lesion in rats.

Therapeutic effect of fluvastatin on medication‐related osteonecrosis of the jaw

“…However, we failed to develop the onset of MRONJ‐like lesions with ZOL alone. Other previous studies were also unable to establish an MRONJ‐like rat or mouse model using ZOL alone, 29,30 which is why we used DEX as an adjuvant to generate MRONJ symptoms, as reported previously 19,22 . A previous report indicated that DEX alone could not create necrotic bone formation when it was administered at the rodent tooth extraction socket 30 .…”

“…Eighteen Wistar rats (female, 4 weeks old, weight 55 to 70 g, two groups) were used in Experiment 1, and 21 rats (three groups) were used in Experiment 2. The sample size was determined based on a previous study 19 …”

“…18 More recently, a single local injection of FS at the time of tooth extraction was reported to have the potential to reduce the chance of developing MRONJ-like lesions in a rat model. 19 In the present study, we hypothesized that the topical administration of FS to the site of MRONJ-like symptoms might promote the healing of MRONJ-like lesions in a rat model. The null hypothesis was that FS has no therapeutic effect on MRONJ-like lesions.…”

“…Furthermore, for oral tissues, fluvastatin (FS) was reported to promote the healing of tooth extraction sockets 18 . More recently, a single local injection of FS at the time of tooth extraction was reported to have the potential to reduce the chance of developing MRONJ‐like lesions in a rat model 19 …”

Replacement Process of Carbonate Apatite by Alveolar Bone in a Rat Extraction Socket

“…Each day after the rats were sacrificed, their maxillae were corrected, and fixed in 4% paraformaldehyde (Merck, Darmstadt, Germany) for 24 h. Micro-computed tomography (micro-CT) imaging was performed by micro-CT (SkyScan 1076, Bruker, Kontich, Belgium) using X-ray energy with a tube current of 201 μA and voltage of 49 kV. Three-dimensional analysis software version 1.18.8 (CTAn, Bruker, Kontich, Belgium) was used for analysis [ 21 ].…”