Bone remodeling during alveolar repair is impaired by RANKL antagonist

Authors

DOI:

https://doi.org/10.33448/rsd-v10i1.11975

Keywords:

Osteoporosis; Bone remodeling; Bone density; Tooth socket; Denosumab.

Abstract

Post-menopausal osteoporosis is detrimental to bone metabolism as well as alveolar repair. This osteometabolic disorder is an obstacle to the success of maxillofacial rehabilitations, since a large number of patients are carriers of the disease. Denosumab is widely used as a treatment for post menopausal osteoporosis. This drug exerts an antiabsorptive action by inhibiting RANKL, helping to reduce the bone loss caused by osteoporosis.  This study aimed to evaluate the repair bone formed after the extraction of the upper incisor of estrogen-deficient rats treated with anti-RANKL monoclonal antibody. The rats (Rattus novergicus albinus, Wistar) were ovariectomized or SHAM operated (n=36). Half of the ovariectomized rats were treated with osteoprotegerin with an Fc fragment (OPG-Fc; 10mg/kg, twice a week), the other half received saline solution as control. After 30 days the rats had their right upper incisor extracted. After 60 days of extraction, the alveoli were evaluated by immunohistochemical, computerized microtomography and confocal microscopy. The OPG-Fc decreased the percentage of bone volume (BV/TV), thickness (Tb.Th) and number of alveolar trabecules (Tb.N) when compared to groups that received saline solution (p<0.005). The OPG-Fc increased the separation between the trabecules (Tb.Sp) and the porosity (Po.tot) of the reparative alveolar bone (p<0.005). The OPG-Fc decreased immunolabelling for RANKL and TRAP when compared to groups that received saline solution. Treatment with OPG-Fc decreased bone neoformation but preserved preexisting bone tissue. This data is supported by the mineral apposition rate, which showed higher values for OVX/OPG-Fc when compared to the OVX group.

References

Adami, S., Libanati, C., Boonen, S., Cummings, S. R., Ho, P. R., Wang, A., Siris, E., Lane, J., FREEDOM Fracture-Healing Writing Group, Adachi, J. D., Bhandari, M., de Gregorio, L., Gilchrist, N., Lyritis, G., Möller, G., Palacios, S., Pavelka, K., Heinrich, R., Roux, C., & Uebelhart, D. (2012). Denosumab treatment in postmenopausal women with osteoporosis does not interfere with fracture-healing: results from the FREEDOM trial. The Journal of bone and joint surgery. American volume, 94(23), 2113–2119. https://doi.org/10.2106/JBJS.K.00774

Aghaloo, T. L., Felsenfeld, A. L., & Tetradis, S. (2010). Osteonecrosis of the jaw in a patient on Denosumab. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons, 68(5), 959–963. https://doi.org/10.1016/j.joms.2009.10.010

Baron, R., Ferrari, S., & Russell, R. G. (2011). Denosumab and bisphosphonates: different mechanisms of action and effects. Bone, 48(4), 677–692. https://doi.org/10.1016/j.bone.2010.11.020

Bouxsein, M. L., Boyd, S. K., Christiansen, B. A., Guldberg, R. E., Jepsen, K. J., & Müller, R. (2010). Guidelines for assessment of bone microstructure in rodents using micro-computed tomography. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 25(7), 1468–1486. https://doi.org/10.1002/jbmr.141

de Oliveira Puttini, I., Gomes-Ferreira, P., de Oliveira, D., Hassumi, J. S., Gonçalves, P. Z., & Okamoto, R. (2019). Teriparatide improves alveolar bone modelling after tooth extraction in orchiectomized rats. Archives of oral biology, 102, 147–154. https://doi.org/10.1016/j.archoralbio.2019.04.007

Eastell R. (1998). Treatment of postmenopausal osteoporosis. The New England journal of medicine, 338(11), 736–746. https://doi.org/10.1056/NEJM199803123381107

Evans, H. M., & Long, J. A. (1922). Characteristic Effects upon Growth, Oestrus and Ovulation Induced by the Intraperitoneal Administration of Fresh Anterior Hypophyseal Substance. Proceedings of the National Academy of Sciences of the United States of America, 8(3), 38–39. https://doi.org/10.1073/pnas.8.3.38

Gallagher J. C. (2008). Advances in bone biology and new treatments for bone loss. Maturitas, 60(1), 65–69. https://doi.org/10.1016/j.maturitas.2008.04.005

Gerstenfeld, L. C., Sacks, D. J., Pelis, M., Mason, Z. D., Graves, D. T., Barrero, M., Ominsky, M. S., Kostenuik, P. J., Morgan, E. F., & Einhorn, T. A. (2009). Comparison of effects of the bisphosphonate alendronate versus the RANKL inhibitor denosumab on murine fracture healing. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 24(2), 196–208. https://doi.org/10.1359/jbmr.081113

Henriksen, K., Neutzsky-Wulff, A. V., Bonewald, L. F., & Karsdal, M. A. (2009). Local communication on and within bone controls bone remodeling. Bone, 44(6), 1026–1033. https://doi.org/10.1016/j.bone.2009.03.671

Ikeda, T., Utsuyama, M., & Hirokawa, K. (2001). Expression profiles of receptor activator of nuclear factor kappaB ligand, receptor activator of nuclear factor kappaB, and osteoprotegerin messenger RNA in aged and ovariectomized rat bones. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 16(8), 1416–1425. https://doi.org/10.1359/jbmr.2001.16.8.1416

Karsdal, M. A., Martin, T. J., Bollerslev, J., Christiansen, C., & Henriksen, K. (2007). Are nonresorbing osteoclasts sources of bone anabolic activity?. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 22(4), 487–494. https://doi.org/10.1359/jbmr.070109

Kostenuik, P. J., Capparelli, C., Morony, S., Adamu, S., Shimamoto, G., Shen, V., Lacey, D. L., & Dunstan, C. R. (2001). OPG and PTH-(1-34) have additive effects on bone density and mechanical strength in osteopenic ovariectomized rats. Endocrinology, 142(10), 4295–4304. https://doi.org/10.1210/endo.142.10.8437

Kostenuik, P. J., Nguyen, H. Q., McCabe, J., Warmington, K. S., Kurahara, C., Sun, N., Chen, C., Li, L., Cattley, R. C., Van, G., Scully, S., Elliott, R., Grisanti, M., Morony, S., Tan, H. L., Asuncion, F., Li, X., Ominsky, M. S., Stolina, M., Dwyer, D., … Sullivan, J. K. (2009). Denosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and increases BMD in knock-in mice that express chimeric (murine/human) RANKL. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 24(2), 182–195. https://doi.org/10.1359/jbmr.081112

Luvizuto, E. R., Queiroz, T. P., Dias, S. M., Okamoto, T., Dornelles, R. C., Garcia, I. R., Jr, & Okamoto, R. (2010). Histomorphometric analysis and immunolocalization of RANKL and OPG during the alveolar healing process in female ovariectomized rats treated with oestrogen or raloxifene. Archives of oral biology, 55(1), 52–59. https://doi.org/10.1016/j.archoralbio.2009.11.001

Manrique, N., Pereira, C. C., Luvizuto, E. R., Sánchez, M., Okamoto, T., Okamoto, R., Sumida, D. H., & Antoniali, C. (2015). Hypertension modifies OPG, RANK, and RANKL expression during the dental socket bone healing process in spontaneously hypertensive rats. Clinical oral investigations, 19(6), 1319–1327. https://doi.org/10.1007/s00784-014-1369-0

Martin T. J. (2004). Does bone resorption inhibition affect the anabolic response to parathyroid hormone?. Trends in endocrinology and metabolism: TEM, 15(2), 49–50. https://doi.org/10.1016/j.tem.2004.01.002

McClung, M. R., Lewiecki, E. M., Cohen, S. B., Bolognese, M. A., Woodson, G. C., Moffett, A. H., Peacock, M., Miller, P. D., Lederman, S. N., Chesnut, C. H., Lain, D., Kivitz, A. J., Holloway, D. L., Zhang, C., Peterson, M. C., Bekker, P. J., & AMG 162 Bone Loss Study Group (2006). Denosumab in postmenopausal women with low bone mineral density. The New England journal of medicine, 354(8), 821–831. https://doi.org/10.1056/NEJMoa044459

Miyazaki, T., Matsunaga, T., Miyazaki, S., Hokari, S., & Komoda, T. (2004). Changes in receptor activator of nuclear factor-kappaB, and its ligand, osteoprotegerin, bone-type alkaline phosphatase, and tartrate-resistant acid phosphatase in ovariectomized rats. Journal of cellular biochemistry, 93(3), 503–512. https://doi.org/10.1002/jcb.20201

Nakamichi, Y., Udagawa, N., Kobayashi, Y., Nakamura, M., Yamamoto, Y., Yamashita, T., Mizoguchi, T., Sato, M., Mogi, M., Penninger, J. M., & Takahashi, N. (2007). Osteoprotegerin reduces the serum level of receptor activator of NF-kappaB ligand derived from osteoblasts. Journal of immunology (Baltimore, Md. : 1950), 178(1), 192–200. https://doi.org/10.4049/jimmunol.178.1.192

Okamoto, T., & de Russo, M. C. (1973). Wound healing following tooth extraction. Histochemical study in rats. Revista da Faculdade de Odontologia de Aracatuba, 2(2), 153–169.

Ominsky, M. S., Li, X., Asuncion, F. J., Barrero, M., Warmington, K. S., Dwyer, D., Stolina, M., Geng, Z., Grisanti, M., Tan, H. L., Corbin, T., McCabe, J., Simonet, W. S., Ke, H. Z., & Kostenuik, P. J. (2008). RANKL inhibition with osteoprotegerin increases bone strength by improving cortical and trabecular bone architecture in ovariectomized rats. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 23(5), 672–682. https://doi.org/10.1359/jbmr.080109

Pedrosa, W. F., Jr, Okamoto, R., Faria, P. E., Arnez, M. F., Xavier, S. P., & Salata, L. A. (2009). Immunohistochemical, tomographic and histological study on onlay bone graft remodeling. Part II: calvarial bone. Clinical oral implants research, 20(11), 1254–1264. https://doi.org/10.1111/j.1600-0501.2009.01747.x

Ramalho-Ferreira, G., Faverani, L. P., Momesso, G., Luvizuto, E. R., de Oliveira Puttini, I., & Okamoto, R. (2017). Effect of antiresorptive drugs in the alveolar bone healing. A histometric and immunohistochemical study in ovariectomized rats. Clinical oral investigations, 21(5), 1485–1494. https://doi.org/10.1007/s00784-016-1909-x

Roodman G. D. (1999). Cell biology of the osteoclast. Experimental hematology, 27(8), 1229–1241. https://doi.org/10.1016/s0301-472x(99)00061-2

Samadfam, R., Xia, Q., & Goltzman, D. (2007). Co-treatment of PTH with osteoprotegerin or alendronate increases its anabolic effect on the skeleton of oophorectomized mice. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 22(1), 55–63. https://doi.org/10.1359/jbmr.060915

Seeman, E., & Delmas, P. D. (2006). Bone quality--the material and structural basis of bone strength and fragility. The New England journal of medicine, 354(21), 2250–2261. https://doi.org/10.1056/NEJMra053077

Simonet, W. S., Lacey, D. L., Dunstan, C. R., Kelley, M., Chang, M. S., Lüthy, R., Nguyen, H. Q., Wooden, S., Bennett, L., Boone, T., Shimamoto, G., DeRose, M., Elliott, R., Colombero, A., Tan, H. L., Trail, G., Sullivan, J., Davy, E., Bucay, N., Renshaw-Gegg, L., … Boyle, W. J. (1997). Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell, 89(2), 309–319. https://doi.org/10.1016/s0092-8674(00)80209-3

Teófilo, J. M., Brentegani, L. G., & Lamano-Carvalho, T. L. (2004). Bone healing in osteoporotic female rats following intra-alveolar grafting of bioactive glass. Archives of oral biology, 49(9), 755–762. https://doi.org/10.1016/j.archoralbio.2004.02.013

Yoneda, T., Ishimaru, N., Arakaki, R., Kobayashi, M., Izawa, T., Moriyama, K., & Hayashi, Y. (2004). Estrogen deficiency accelerates murine autoimmune arthritis associated with receptor activator of nuclear factor-kappa B ligand-mediated osteoclastogenesis. Endocrinology, 145(5), 2384–2391. https://doi.org/10.1210/en.2003-1536

Zhao, C., Irie, N., Takada, Y., Shimoda, K., Miyamoto, T., Nishiwaki, T., Suda, T., & Matsuo, K. (2006). Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis. Cell metabolism, 4(2), 111–121. https://doi.org/10.1016/j.cmet.2006.05.012

Downloads

Published

24/01/2021

How to Cite

SILVA, A. C. E. da .; BATISTA, F. R. de S. .; MOURA, J. de .; COLÉTE, J. Z. .; CHIBA, F. .; GOMES-FERREIRA, P. H. S. .; OKAMOTO, R. . Bone remodeling during alveolar repair is impaired by RANKL antagonist. Research, Society and Development, [S. l.], v. 10, n. 1, p. e43710111975, 2021. DOI: 10.33448/rsd-v10i1.11975. Disponível em: https://rsdjournal.org/index.php/rsd/article/view/11975. Acesso em: 22 nov. 2024.

Issue

Vol. 10 No. 1

Section

Health Sciences

License

Copyright (c) 2021 Ana Cláudia Ervolino da Silva; Fábio Roberto de Souza Batista; Juliana de Moura; Juliana Zorzi Coléte; Fernando Chiba; Pedro Henrique Silva Gomes-Ferreira; Roberta Okamoto

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Authors who publish with this journal agree to the following terms:

1) Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.

2) Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.

3) Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work.