Relationship between different doses of zoledronic acid and bisphosphonate-related osteonecrosis of jaw: an experiment study in rats

doi:10.19438/j.cjoms.2017.02.004

Abstract

Abstract: PURPOSE : To investigate the relationship between different doses of zoledronic acid (ZA) and bisphosphonate-related osteonecrosis of jaw (BRONJ) by establishing the model of osteonecrosis of jaw in rats with different doses of ZA. METHODS : Forty SD rats were divided into 4 groups (ten rats in each group), the rats in 4 groups were injected intraperitoneally with 33, 66 and 132 μg/kg ZA or normal saline (control), respectively, three times a week for 12 weeks, and the weight was measured weekly. In the ninth week, all rats was subjected to extraction of the first left mandibular molar. After the last injection, all rats were sacrificed. The jaws were clinically, radiologically and histopathologically examined. Independent samples t test was performed using SPSS19.0 software package. RESULTS : The weight of rats in the experimental groups was significantly lower than that in the control group after extraction (P<0.05). 86.7% rats in the experimental group were observed with unclosed mucosa; however, mucosa on extraction sites in the control group healed completely (P<0.05). Radiological examination revealed radiolucent areas on the extraction sites in the experimental groups were significantly greater than those in the control group (P<0.05). Histopathological examination showed 70% rats in the experimental group developed osteonecrosis,especially in higher dose group,while osteonecrosis was not found in the control group (P<0.05). CONCLUSION : The study showed severe BRONJ was closely associated with high dose of ZA. Low dose of ZA just induces minor BRONJ, or is unable to induce BRONJ. Thus, Patients treated with high dose of ZA are facing great risk of developing BRONJ.

Key words: Zoledronic Acid, Dose, Jaw, Osteonecrosis

CLC Number:

R782

SHEN Ya-jun, DU Ming-yan, GUAN Jian, LI Mao, ZHAO Yan-tao, GE Cheng. Relationship between different doses of zoledronic acid and bisphosphonate-related osteonecrosis of jaw: an experiment study in rats[J]. China Journal of Oral and Maxillofacial Surgery, 2017, 15(2): 115-120.

References

[1] Ruggiero SL, Dodson TB, Fantasia J, et al. American association of oral and maxillofacial surgeons position paper on medication-related osteonecrosis of the jaw-2014 update [J]. J Oral Maxillofac Surg, 2014, 72(10):1938-1956.
[2] Guarneri V, MilesD, Robert N, et al. Bevacizumab and osteonecrosis of the jaw: incidence and association with bisphosphonate therapy in three large prospective trials in advanced breast cancer [J]. Breast Cancer Res Treat, 2010, 122(1): 181-188.
[3] Barasch A, Cunha-Cruz J, Curro FA, et al. Risk factors for osteonecrosis of the jaws: a case-control study from the CONDOR dental PBRN [J]. J Dent Res, 2011, 90(4): 439-444.
[4] Yamazaki T, Yamori M, Ishizaki T, et al. Increased incidence of osteonecrosis of the jaw after tooth extraction in patients treated with bisphosphonates: a cohort study [J]. Int J Oral Maxillofac Surg, 2012, 41(11): 1397-1403.
[5] Allen MR. The effects of bisposphonates on jaw bone remodeling, tissue proprieties, and extraction healing [J]. Odontology, 2011, 99(1): 8-17.
[6] Aghaloo TL, Kang B, Sung EC, et al. Periodontal disease and bisphosphonates induce osteonecrosis of the jaws in the rat[J]. J Bone Miner Res, 2011, 26(8): 1871-1882.
[7] Jabbour Z, El-Hakim M, Henderson JE, et al. Bisphosphonates inhibit bone remodeling in the jaws bones of rats and delay healing following tooth extractions [J]. Oral Oncol, 2014, 50(5): 485-490.
[8] Aghaloo TL, Kang B, Sung EC, et al. Periodontal disease and bisphosphonates induce osteonecrosis of the jaws in the rat [J]. J Bone Miner Res, 2011, 26(8): 1871-1882.
[9] Kang B, Cheong S, Chaichanasakul T, et al. Periapical disease and bisphosphonates induce osteonecrosis of the jaws in mice [J]. Bone Miner Res, 2013, 28(7): 1631-1640.
[10] Sonis ST, Watkins BA, Lyng GD, et al. Bony changes in the jaws of rats treated with zoledronic acid and dexamethasone before dental extractions mimic bisphosphonate-related osteonecrosis in cancer patients [J]. Oral Oncol, 2009, 45(2): 164-172.
[11] Li CL, Seneviratne CJ, Huo L, et al. Impact of Actinomyces naeslundii on bisphosphonate-related osteonecrosis of the jaws in ovariectomized rats with periodontitis[J]. J Cranio maxillofac Surg, 2015, 43(8): 1662-1669.
[12] Roelofs AJ, Thompson K, Gordon S, et al. Molecular mechanisms of action of bisphosphonates: current status [J]. Clin Cancer Res, 2006, 12(20 Pt 2): 6222s-6230s.
[13] Vasconcelos AC, Berti-Couto SA, Azambuja AA, et al. Comparison of effects of clodronate and zoledronic acid on the repair of maxilla surgical wounds histomorphometric, receptor activator of nuclear factor-kB ligand, osteoprotegerin, von Willebrand factor, and caspase-3 evaluation[J]. J Oral Pathol Med, 2012, 41(9): 702-712.
[14] Mavrokokki T, Cheng A, Stein B, et al. Nature and frequency of bisphosphonate-associated osteonecrosis of the jaws in Australia [J]. J Oral Maxillofac Surg, 2007, 65(3): 415-423.
[15] Ersan N, van Ruijven LJ, Bronckers AL, et al. Teriparatide and the treatment of bisphosphonate-related osteonecrosis of the jaw: a rat model [J]. Dentomaxillofac Radiol, 2014, 43(1): 20130144.
[16] Cankaya AB, Erdem MA, Isler SC, et al. Use of cone-beam computerized tomography for evaluation of bisphosphonate-associated osteonecrosis of the jaws in an experimental rat model [J]. Int J Med Sci, 2011, 8(8): 667-672.
[17] Ma YL, Bryant HU, Zeng Q, et al. New bone formation with teriparatide [human parathyroid hormone-(1-34)] is not retarded by long-term pretreatment with alendronate, estrogen, or raloxifene in ovariectomized rats [J]. Endocrinology, 2003, 144(5): 2008-2015.