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Strontium ranelate improves post-extraction socket healing in rats submitted to the administration of bisphosphonates

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Abstract

The aim of this study was to evaluate the effect of strontium ranelate (Sr) on post-extraction socket healing in rats submitted to the administration of bisphosphonates. Sixty rats were submitted to the tooth extraction of the first lower molar after 60 days of the daily administration of saline solution (SS) or alendronate (ALN). Then, the animals were allocated into six groups namely CTR: administration of SS during the whole experiment, ALN: administration of ALN during the whole experiment, ALN/SS: application of SS for 30 days after extraction in animals previously treated with ALN, ALN/Sr: application of Sr for 30 days after extraction in animals previously treated with ALN, ALN/S60: ALN therapy interruption 30 days before the extraction followed by the application of SS for 60 days, and ALN/Sr60: ALN therapy interruption 30 days before the tooth extraction followed by the application of Sr for 60 days. The healing of the post-extraction sockets was evaluated by microCT and histomorphometry. The use of ALN induced partial bone necrosis, inflammatory infiltration, and a delay in soft tissue healing; the use of Sr improved the connective tissue organization. Sr has subtle positive effects on the post-extraction healing in animals submitted to the administration of bisphosphonate.

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Adapted from Conte Neto et al. [21])

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References

  1. Kuznik A, Pazdzierniok-Holewa A, Jewula P, Kuznik N. Bisphosphonates-much more than only drugs for bone diseases. Eur J Pharmacol. 2020;866: 172773. https://doi.org/10.1016/j.ejphar.2019.172773.

    Article  PubMed  Google Scholar 

  2. Ying ZM, Hu B, Yan SG. Oral bisphosphonate therapy for osteogenesis imperfecta: a systematic review and meta-analysis of six randomized placebo-controlled trials. Orthop Surg. 2020;12:1293–303. https://doi.org/10.1111/os.12611.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Russell RG. Bisphosphonates: the first 40 years. Bone. 2011;49:2–19. https://doi.org/10.1016/j.bone.2011.04.022.

    Article  PubMed  Google Scholar 

  4. Borromeo GL, Brand C, Clement JG, McCullough M, Crighton L, Hepworth G, Wark JD. Bisphosphonate exposure and osteonecrosis of the jaw. J Bone Miner Res. 2015;30:749–50. https://doi.org/10.1002/jbmr.2428.

    Article  PubMed  Google Scholar 

  5. Molvik H, Khan W. Bisphosphonates and their influence on fracture healing: a systematic review. Osteoporos Int. 2015;26:1251–60. https://doi.org/10.1007/s00198-014-3007-8.

    Article  PubMed  Google Scholar 

  6. Hou M, Lee RSB, Du Z, Hamlet SM, Vaquette C, Ivanovski S. The influence of high-dose systemic zoledronate administration on osseointegration of implants with different surface topography. J Periodontal Res. 2019;54:633–43. https://doi.org/10.1111/jre.12664.

    Article  PubMed  Google Scholar 

  7. Shudo A, Kishimoto H, Takaoka K, Noguchi K. Long-term oral bisphosphonates delay healing after tooth extraction: a single institutional prospective study. Osteoporos Int. 2018;29:2315–21. https://doi.org/10.1007/s00198-018-4621-7.

    Article  PubMed  Google Scholar 

  8. Imada M, Yagyuu T, Ueyama Y, Maeda M, Yamamoto K, Kurokawa S, Jo JI, Tabata Y, Tanaka Y, Kirita T. Prevention of tooth extraction-triggered bisphosphonate-related osteonecrosis of the jaws with basic fibroblast growth factor: an experimental study in rats. PLoS ONE. 2019;14: e0211928. https://doi.org/10.1371/journal.pone.0211928.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Zang X, He L, Zhao L, He Y, Xiao E, Zhang Y. Adipose-derived stem cells prevent the onset of bisphosphonate-related osteonecrosis of the jaw through transforming growth factor beta-1-mediated gingival wound healing. Stem Cell Res Ther. 2019;10:169. https://doi.org/10.1186/s13287-019-1277-y.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Hasegawa T, Kawakita A, Ueda N, Funahara R, Tachibana A, Kobayashi M, Kondou E, Takeda D, Kojima Y, Sato S, Yanamoto S, Komatsubara H, Umeda M, Kirita T, Kurita H, Shibuya Y, Japanese Study Group of Cooperative Dentistry with M. A multicenter retrospective study of the risk factors associated with medication-related osteonecrosis of the jaw after tooth extraction in patients receiving oral bisphosphonate therapy: can primary wound closure and a drug holiday really prevent MRONJ? Osteoporos Int. 2017;28:2465–73. https://doi.org/10.1007/s00198-017-4063-7.

    Article  PubMed  Google Scholar 

  11. Colapinto G, Volpi R, Forino G, Tricarico V, De Benedittis M, Cortelazzi R, Testori T, Del Fabbro M. Patients’ osteometabolic control improves the management of medication-related osteonecrosis of the jaw. Oral Surg Oral Med Oral Pathol Oral Radiol. 2018;125:147–56. https://doi.org/10.1016/j.oooo.2017.10.015.

    Article  PubMed  Google Scholar 

  12. de Molon RS, Shimamoto H, Bezouglaia O, Pirih FQ, Dry SM, Kostenuik P, Boyce RW, Dwyer D, Aghaloo TL, Tetradis S. OPG-Fc but not zoledronic acid discontinuation reverses osteonecrosis of the jaws (ONJ) in mice. J Bone Miner Res. 2015;30:1627–40. https://doi.org/10.1002/jbmr.2490.

    Article  PubMed  Google Scholar 

  13. Busse B, Jobke B, Hahn M, Priemel M, Niecke M, Seitz S, Zustin J, Semler J, Amling M. Effects of strontium ranelate administration on bisphosphonate-altered hydroxyapatite: matrix incorporation of strontium is accompanied by changes in mineralization and microstructure. Acta Biomater. 2010;6:4513–21. https://doi.org/10.1016/j.actbio.2010.07.019.

    Article  PubMed  Google Scholar 

  14. Marie PJ, Felsenberg D, Brandi ML. How strontium ranelate, via opposite effects on bone resorption and formation, prevents osteoporosis. Osteoporos Int. 2011;22:1659–67. https://doi.org/10.1007/s00198-010-1369-0.

    Article  PubMed  Google Scholar 

  15. Yamaguchi M, Weitzmann MN. The intact strontium ranelate complex stimulates osteoblastogenesis and suppresses osteoclastogenesis by antagonizing NF-kappaB activation. Mol Cell Biochem. 2012;359:399–407. https://doi.org/10.1007/s11010-011-1034-8.

    Article  PubMed  Google Scholar 

  16. Bakker AD, Zandieh-Doulabi B, Klein-Nulend J. Strontium ranelate affects signaling from mechanically-stimulated osteocytes towards osteoclasts and osteoblasts. Bone. 2013;53:112–9. https://doi.org/10.1016/j.bone.2012.11.044.

    Article  PubMed  Google Scholar 

  17. Quade M, Vater C, Schlootz S, Bolte J, Langanke R, Bretschneider H, Gelinsky M, Goodman SB, Zwingenberger S. Strontium enhances BMP-2 mediated bone regeneration in a femoral murine bone defect model. J Biomed Mater Res B Appl Biomater. 2020;108:174–82. https://doi.org/10.1002/jbm.b.34376.

    Article  PubMed  Google Scholar 

  18. Fromigue O, Hay E, Barbara A, Petrel C, Traiffort E, Ruat M, Marie PJ. Calcium sensing receptor-dependent and receptor-independent activation of osteoblast replication and survival by strontium ranelate. J Cell Mol Med. 2009;13:2189–99. https://doi.org/10.1111/j.1582-4934.2009.00673.x.

    Article  PubMed  Google Scholar 

  19. Kapur S, Chen ST, Baylink DJ, Lau KH. Extracellular signal-regulated kinase-1 and -2 are both essential for the shear stress-induced human osteoblast proliferation. Bone. 2004;35:525–34. https://doi.org/10.1016/j.bone.2004.04.007.

    Article  PubMed  Google Scholar 

  20. Rybchyn MS, Islam KS, Brennan-Speranza TC, Cheng Z, Brennan SC, Chang W, Mason RS, Conigrave AD. Homer1 mediates CaSR-dependent activation of mTOR complex 2 and initiates a novel pathway for AKT-dependent beta-catenin stabilization in osteoblasts. J Biol Chem. 2019;294:16337–50. https://doi.org/10.1074/jbc.RA118.006587.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Conte Neto N, Spolidorio LC, Andrade CR, Bastos AS, Guimarães M, Marcantonio E Jr. Experimental development of bisphosphonate-related osteonecrosis of the jaws in rodents. Int J Exp Pathol. 2013;94(1):65–73. https://doi.org/10.1111/iep.12007.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Lavet C, Mabilleau G, Chappard D, Rizzoli R, Ammann P. Strontium ranelate stimulates trabecular bone formation in a rat tibial bone defect healing process. Osteoporos Int. 2017;28:3475–87. https://doi.org/10.1007/s00198-017-4156-3.

    Article  PubMed  Google Scholar 

  23. Lattouf R, Younes R, Lutomski D, Naaman N, Godeau G, Senni K, Changotade S. Picrosirius red staining: a useful tool to appraise collagen networks in normal and pathological tissues. J Histochem Cytochem. 2014;62:751–8. https://doi.org/10.1369/0022155414545787.

    Article  PubMed  Google Scholar 

  24. Aguirre JI, Altman MK, Vanegas SM, Franz SE, Bassit AC, Wronski TJ. Effects of alendronate on bone healing after tooth extraction in rats. Oral Dis. 2010;16:674–85. https://doi.org/10.1111/j.1601-0825.2010.01677.x.

    Article  PubMed  Google Scholar 

  25. Diaz-Borjon A, Seyler TM, Chen NL, Lim SS. Bisphosphonate-associated arthritis. J Clin Rheumatol. 2006;12:131–3. https://doi.org/10.1097/01.rhu.0000221796.06383.4e.

    Article  PubMed  Google Scholar 

  26. Koth VS, Salum FG, de Figueiredo MAZ, Cherubini K. Morphological and immunohistochemical features of tooth extraction sites in rats treated with alendronate, raloxifene, or strontium ranelate. Clin Oral Investig. 2021;25:2705–16. https://doi.org/10.1007/s00784-020-03585-x.

    Article  PubMed  Google Scholar 

  27. Diaz DH, Rodas JA, Bozzini CE, Mandalunis PM, Escudero ND. Sequential administration of alendronate and strontium ranelate: histomorphometry and bone biomechanics in ovariectomized animals. Acta Odontol Latinoam. 2016;29:168–77.

    PubMed  Google Scholar 

  28. Kang SH, Park SJ, Kim MK. The effect of bisphosphonate discontinuation on the incidence of postoperative medication-related osteonecrosis of the jaw after tooth extraction. J Korean Assoc Oral Maxillofac Surg. 2020;46:78–83. https://doi.org/10.5125/jkaoms.2020.46.1.78.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Otto S, Pautke C, Arens D, Poxleitner P, Eberli U, Nehrbass D, Zeiter S, Stoddart MJ. A drug holiday reduces the frequency and severity of medication-related osteonecrosis of the jaw in a Minipig model. J Bone Miner Res. 2020;35:2179–92. https://doi.org/10.1002/jbmr.4119.

    Article  PubMed  Google Scholar 

  30. Ottesen C, Schiodt M, Gotfredsen K. Efficacy of a high-dose antiresorptive drug holiday to reduce the risk of medication-related osteonecrosis of the jaw (MRONJ): a systematic review. Heliyon. 2020;6: e03795. https://doi.org/10.1016/j.heliyon.2020.e03795.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Zandi M, Dehghan A, Ghadermazi K, Malekzadeh H, Akbarzadeh M. Perioperative discontinuation of intravenous bisphosphonate therapy reduces the incidence and severity of bisphosphonate-related osteonecrosis of the jaw: a randomized, controlled, prospective experimental study in rats. J Craniomaxillofac Surg. 2015;43:1823–8. https://doi.org/10.1016/j.jcms.2015.08.008.

    Article  PubMed  Google Scholar 

  32. Barrionuevo P, Kapoor E, Asi N, Alahdab F, Mohammed K, Benkhadra K, Almasri J, Farah W, Sarigianni M, Muthusamy K, Al Nofal A, Haydour Q, Wang Z, Murad MH. Efficacy of pharmacological therapies for the prevention of fractures in postmenopausal women: a network meta-analysis. J Clin Endocrinol Metab. 2019;104:1623–30. https://doi.org/10.1210/jc.2019-00192.

    Article  PubMed  Google Scholar 

  33. Miranda TS, Napimoga MH, De Franco L, Marins LM, Malta FS, Pontes LA, Morelli FM, Duarte PM. Strontium ranelate improves alveolar bone healing in estrogen-deficient rats. J Periodontol. 2020;91:1465–74. https://doi.org/10.1002/JPER.19-0561.

    Article  PubMed  Google Scholar 

  34. Scardueli CR, Bizelli-Silveira C, Marcantonio RAC, Marcantonio E Jr, Stavropoulos A, Spin-Neto R. Systemic administration of strontium ranelate to enhance the osseointegration of implants: systematic review of animal studies. Int J Implant Dent. 2018;4:21. https://doi.org/10.1186/s40729-018-0132-8.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Pan WL, Chen PL, Lin CY, Pan YC, Ju YR, Chan CP, Hsu RW. Strontium ranelate treatment in a postmenopausal woman with osteonecrosis of the jaw after long-term oral bisphosphonate administration: a case report. Clin Interv Aging. 2017;12:1089–93. https://doi.org/10.2147/CIA.S141753.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES) and CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico). The authors declare to have no conflicts of interesting regarding this paper.

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Authors and Affiliations

  1. Department of Diagnosis and Surgery, School of Dentistry, São Paulo State University (Unesp), Humaitá St., 1680, Araraquara, SP, 14801-930, Brazil

    Fernanda Castanheira Gonçalves, Bruno Arruda Mascaro, Cássio Rocha Scardueli & Rosemary Adriana Chierici Marcantonio

  2. Department of Periodontology/Implantology, Dental School, UFU - Universidade Federal de Uberlândia, Uberlândia, MG, Brazil

    Guilherme José Pimentel Lopes de Oliveira

  3. Department of Physiology and Pathology, School of Dentistry, São Paulo State University (Unesp), Humaitá St., 1680, Araraquara, 14801-930, Brazil

    Luis Carlos Spolidorio

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  1. Fernanda Castanheira Gonçalves
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Gonçalves, F.C., Mascaro, B.A., Scardueli, C.R. et al. Strontium ranelate improves post-extraction socket healing in rats submitted to the administration of bisphosphonates. Odontology 110, 467–475 (2022). https://doi.org/10.1007/s10266-021-00678-1

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