ABSTRACT
BACKGROUND: Although zoledronic acid can effectively prevent bone loss in postmenopausal women, its effect and mechanism on the mandible are not clarified. OBJECTIVE: To study the morphological and pathological changes of mandibular tissue in ovariectomized rats treated with low-dose zoledronic acid and to investigate the regulatory effect and mechanism of RANKL/RANK/OPG signaling system in the inhibition of bone resorption by zoledronic acid. METHODS: Thirty-six adult female Sprague-Dawley rats were randomized into control, model and treatment groups. Animal models of osteoporosis were made by bilateral ovariectomy in the latter two groups, while the same amount of lipid tissues surrounding the ovary was removed in the control group. Three weeks after ovariectomy, the rats in the treatment group were given subcutaneous injection of 20 µg/kg zoledronic acid. The corresponding doses of saline were injected subcutaneously in the control and model groups. One week after treatment, the left mandibular molars were extracted from all the rats, and the rats’ jaws were separated and removed at 4 weeks after tooth extraction for detection. The residual alveolar bone of the extracted socket was observed by X-ray. The pathological changes of the mandibular cortex and cancellous bone were detected by hematoxylin-eosin staining. The number of apoptotic osteoblasts was detected by TUNEL apoptosis test. The expressions of receptor activator of nuclear factor-κ B ligand (RANKL), osteoprotegerin and nuclear transcription factor-κB (NF-κB) in the mandibular alveolar bone were detected by immunohistochemical technique. Western blot was finally used to detect the expression of RANKL and NF-κB at protein levels. RESULTS AND CONCLUSION: (1) At 4 week after tooth extract, subcutaneous injection of 20 µg/kg zoledronic acid effectively inhibited alveolar bone resorption and promoted new bone formation at the extraction socket. (2) Hematoxylin-eosin staining results showed that: in the model group, the cortical bone was thinned, and the trabecular bone was thinned and even ruptured. There were a large number of bone resorption lacunae but few osteoblasts in the model group. In the treatment group, the cortical bone was thickened and the trabecular bone had normal structure, with only a small amount of bone resorption lacunae and increased number of osteoblasts. (3) The number of apoptotic osteoblasts was significantly lower in the treatment group than the model group (P < 0.001). (4) Immunohistochemical staining results showed significantly decreased RANKL and NF-κB protein expressions (P < 0.001, P < 0.002) and significantly increased osteoprotegerin level (P < 0.001) in the treatment group than the model group. (5) Western blot results revealed that the protein expressions of RANKL and NF-κB in the model group were significantly higher than those in the control group, and treatment with zoledronic acid significantly reduced these protein levels (both P < 0.001). To conclude, zoledronic acid could inhibit the differentiation of osteoclasts by down-regulating the NF-κB signal pathway and meanwhile regulate the apoptosis of osteoblasts.
ABSTRACT
BACKGROUND: Zoledronic acid can effectively enhance dental implant osseointegration, but it can also impair soft tissue and blood supply around the implant, eventually leading to bisphosphonate-associated osteonecrosis of the jaw. Therefore, it is a problem highly valued in implant restorations. OBJECTIVE: To review the application of zoledronic acid in the dental implantation after osteoporosis. METHODS: The first author searched PubMed and CNKI using computer for relevant articles concerning the potential mechanism by which zoledronic acid promotes dental implant osseointegration as well as its application in vitro and in vivo. The key words were "bisphosphonate, zoledronic acid, implant, osseointegration" in English and Chinese, respectively. RESULTS AND CONCLUSION: Zoledronic acid has been demonstrated to inhibit bone resorption and promote bone formation via local or systemic use, single or combined use with other drugs. However, the inhibition of osteoclasts by zoledronic acid is associated with the dose and action time of zoledronic acid. Thus, further investigation on the specific mechanisms of zoledronic acid at different dose and with different action time are warranted. We should further elucidate the risk factors and determinants of osteonecrosis of the jaw through clinical studies, and then find effective approaches to reduce the risk of jaw osteonecrosis and to maximize the positive effect of zoledronic acid in the dental implantation.