Abstract
Objective
The aim of this study was to evaluate morphological and immunohistochemical features of tooth extraction sites in rats subjected to different antiresorptive drugs.
Materials and methods
Wistar rats were allocated into 4 groups according to the treatment: (1) alendronate, (2) raloxifene, (3) strontium ranelate, and (4) control. The animals underwent tooth extraction (60th day of treatment) and afterwards were euthanized (90th day of treatment). Tooth extraction sites were analyzed by means of scanning electron microscopy (SEM), hematoxylin-eosin staining (H&E), and immunohistochemical staining (RANKL and OPG).
Results
On H&E analysis, the alendronate group showed greater amounts of non-vital bone, biofilm, inflammatory infiltrate and root fragment, and smaller amount of vital bone. The strontium ranelate group showed great amount of non-vital bone. This group also had lower levels of OPG, while the alendronate group showed lower OPG and RANKL than the other groups. On SEM analysis, the alendronate group showed a considerable number of microcracks on the alveolar bone surface and few Howship lacunae and lack of bone cells as well. The raloxifene, strontium ranelate, and control groups showed a large number of bone cells and Howship lacunae on the bone surface and few microcracks.
Conclusion
Alendronate therapy is associated with macro- and microscopic features of medication-related osteonecrosis of the jaw at tooth extraction sites, whereas raloxifene therapy is not, and strontium ranelate therapy is associated with non-vital bone.
Clinical relevance
Osteonecrosis of the jaws is a serious side effect of alendronate therapy, where tooth extraction is a major risk factor. Considering the significant number of patients undergoing antiresorptive therapies worldwide, the present study investigated whether raloxifene and strontium ranelate interfere with bone repair after tooth extraction in a similar way to bisphosphonates.
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References
Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, O'Ryan F, American Association of Oral and Maxillofacial Surgeons (2014) American association of oral and maxillofacial surgeons position paper on medication-related osteonecrosis of the jaw - 2014 update. J Oral Maxillofac Surg 72:1938–1956. https://doi.org/10.1016/j.joms.2014.04.031
Hayashida S, Yanamoto S, Fujita S, Hasegawa T, Komori T, Kojima Y, Miyamoto H, Shibuya Y, Ueda N, Kirita T, Nakahara H, Shinohara M, Kondo E, Kurita H, Umeda M (2020) Drug holiday clinical relevance verification for antiresorptive agents in medication-related osteonecrosis cases of the jaw. J Bone Miner Metab 38:126–134. https://doi.org/10.1007/s00774-019-01035-7
Zandi M, Dehghan A, Ghadermazi K, Malekzadeha H, Akbarzadeh M (2015) 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 Cranio-Maxillofac Surg 43:1823–1828. https://doi.org/10.1016/j.jcms.2015.08.008
Ramaglia L, Guida A, Iorio-Siciliano V, Cuozzo A, Blasi A, Sculean A (2018) Stage-specific therapeutic strategies of medication-related osteonecrosis of the jaws: a systematic review and meta-analysis of the drug suspension protocol. Clin Oral Investig 22:597–615. https://doi.org/10.1007/s00784-017-2325-6
Pavone V, Testa G, Giardina SMC, Andrea V, Domenico AR, Giuseppe S (2017) Pharmacological therapy of osteoporosis: a systematic current review of literature. Front Pharmacol 8:1–7. https://doi.org/10.3389/fphar.2017.00803
Jung J, Park JS, Righesso L, Pabst AM, al-Nawas B, Kwon YD, Walter C (2018) Effects of an oral bisphosphonate and three intravenous bisphosphonates on several cell types in vitro. Clin Oral Investig 22:2527–2534. https://doi.org/10.1007/s00784-018-2349-6
Cremers S, Drake MT, Ebetino FH, Bilezikian JP, Russell RGG (2019) Pharmacology of bisphosphonates. Br J Clin Pharmacol 85:1052–1062. https://doi.org/10.1111/bcp.13867
Cosman F, de Beur SJ, LeBoff MS, Lewiecki EM, Tanner B, Randall S, Lindsay R (2014) Clinician’s guide to prevention and treatment of osteoporosis. Osteoporos Int 25:2359–2381. https://doi.org/10.1007/s00198-014-2794-2
Shoback D, Rosen CJ, Black DM, Cheung AM, Murad MH, Eastell R (2020) Pharmacological management of osteoporosis in postmenopausal women: an endocrine society guideline update. J Clin Endocrinol Metab 105:587–594. https://doi.org/10.1210/clinem/dgaa048
Limones A, Sáez-Alcaide LM, Díaz-Parreño SA, Helm A, Bornstein MM, Molinero-Mourelle P (2020) Medication-related osteonecrosis of the jaws (MRONJ) in cancer patients treated with denosumab VS. zoledronic acid: a systematic review and meta-analysis. Med Oral Patol Oral Cir Bucal 25:e326–e336. https://doi.org/10.4317/medoral.23324
Williams DW, Lee C, Kim T, Yagita H, Wu H, Park S, Yang P, Liu H, Shi S, Shin KH, Kang MK, Park NH, Kim RH (2014) Impaired bone resorption and woven bone formation are associated with development of osteonecrosis of the jaw-like lesions by bisphosphonate and anti-receptor activator of NF-κB ligand antibody in mice. Am J Pathol 184:3084–3093. https://doi.org/10.1016/j.ajpath.2014.07.010
Baur DA, Altay MA, Teich S, Oswald SM, Quereshy FA (2015) Osteonecrosis of the jaw in a patient on raloxifene: a case report. Quintessence Int 46:423–428. https://doi.org/10.3290/j.qi.a32918
Chiu WY, Chien JY, Yang WS, Juang JJM, Lee JJ, Tsai KS (2014) The risk of osteonecrosis of the jaws in Taiwanese osteoporotic patients treated with oral alendronate or raloxifene. J Clin Endocrinol Metab 99:2729–2735. https://doi.org/10.1210/jc.2013-4119
Rebelo Pontes HA, de Souza LL, Colares Uchôa DC, Mendes Cerqueira JM (2018) Mandibular osteonecrosis associated with raloxifene. J Craniofac Surg 29:e257–e259. https://doi.org/10.1097/SCS.0000000000004278
Longato L, Cavalli L, Marcucci G et al (2013) Osteonecrosis of the jaw in a patient with rheumatoid arthritis treated with an oral aminobisphosphonate: a clinical case report. Clin Cases Miner Bone Metab 10:139–141. https://doi.org/10.11138/ccmbm/2013.10.2.139
Notarnicola A, Lisi S, Sisto M, de Marino AV, D'Amore M (2012) Possible role of oral ibandronate administration in osteonecrosis of the jaw: A case report. Int J Immunopathol Pharmacol 25:311–316. https://doi.org/10.1177/039463201202500138
Pan WL, Chen PL, Lin CY, Pan YC, Ju YR, Chan CP, Hsu RW (2017) Strontium ranelate treatment in a postmenopausal woman with osteonecrosis of the jaw after long-term oral bisphosphonate administration: A case report. Clin Interv Aging 12:1089–1093. https://doi.org/10.2147/CIA.S141753
Rahim I, Salt S, Heliotis M (2015) Successful long-term mandibular reconstruction and rehabilitation using non-vascularised autologous bone graft and recombinant human BMP-7 with subsequent endosseous implant in a patient with bisphosphonate-related osteonecrosis of the jaw. Br J Oral Maxillofac Surg 53:870–874. https://doi.org/10.1016/j.bjoms.2015.08.006
Chattopadhyay I, Verma M, Panda M (2019) Role of oral microbiome signatures in diagnosis and prognosis of oral cancer. Technol Cancer Res Treat 18:1–19. https://doi.org/10.1177/1533033819867354
Dahl SG, Allain P, Marie PJ, Mauras Y, Boivin G, Ammann P, Tsouderos Y, Delmas PD, Christiansen C (2001) Incorporation and distribution of strontium in bone. Bone 28:446–453. https://doi.org/10.1016/S8756-3282(01)00419-7
Saidak Z, Marie PJ (2012) Strontium signaling: molecular mechanisms and therapeutic implications in osteoporosis. Pharmacol Ther 136:216–226. https://doi.org/10.1016/j.pharmthera.2012.07.009
Rey JRC, Cervino EV, Rentero ML, Crespo EC, Álvaro AO, Marta CM (2009) Raloxifene: mechanism of action, effects on bone tissue, and applicability in clinical traumatology practice. Open Orthop J 3:14–21. https://doi.org/10.2174/1874325000903010014
Cranney A, Adachi JD (2005) Benefit-risk assessment of raloxifene in postmenopausal osteoporosis. Drug Saf 28:721–730. https://doi.org/10.2165/00002018-200528080-00006
Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG (2010) Improving bioscience research reporting: The arrive guidelines for reporting animal research. PLoS Biol 8:6–10. https://doi.org/10.1371/journal.pbio.1000412
Edition E (2010) Guide for the care and use of laboratory animals, 8th edn. The national academies press, Washington DC
Berti-Couto SA, Vasconcelos ACU, Iglesias JE, Figueiredo MAZ, Salum FG, Cherubini K (2014) Diabetes mellitus and corticotherapy as risk factors for alendronate-related osteonecrosis of the jaws: A study in Wistar rats. Head Neck 36:84–93. https://doi.org/10.1002/hed.23260
Luvizuto ER, Dias SMD, Queiroz TP, Okamoto T, Garcia IR Jr, Okamoto R, Dornelles RCM (2010) Osteocalcin immunolabeling during the alveolar healing process in ovariectomized rats treated with estrogen or raloxifene. Bone 46:1021–1029. https://doi.org/10.1016/j.bone.2009.12.016
Bain SD, Jerome C, Shen V, Dupin-Roger I, Ammann P (2009) Strontium ranelate improves bone strength in ovariectomized rat by positively influencing bone resistance determinants. Osteoporos Int 20:1417–1428. https://doi.org/10.1007/s00198-008-0815-8
Silva ML, Tasso L, Azambuja AA, Figueiredo MA, Salum FG, Silva VD, Cherubini K (2017) Effect of hyperbaric oxygen therapy on tooth extraction sites in rats subjected to bisphosphonate therapy—histomorphometric and immunohistochemical analysis. Clin Oral Investig:21–210. https://doi.org/10.1007/s00784-016-1778-3
Maahs MP, Azambuja AA, Campos MM, Salum FG, Cherubini K (2011) Association between bisphosphonates and jaw osteonecrosis: A study in Wistar rats. Head Neck 33:199–207. https://doi.org/10.1002/hed.21422
Close B, Banister K, Baumans V, Bernoth EM, Bromage N, Bunyan J, Erhardt W, Flecknell P, Gregory N, Hackbarth H, Morton D, Warwick C (1997) Recommendations for euthanasia of experimental animals: Part 2. Lab Anim 31:1–32. https://doi.org/10.1258/002367797780600297
Ramchand SK, Seeman E (2018) Advances and unmet needs in the therapeutics of bone fragility. Front Endocrinol (Lausanne) 9:1–10. https://doi.org/10.3389/fendo.2018.00505
Allen MR, Burr DB (2011) Bisphosphonate effects on bone turnover, microdamage, and mechanical properties: What we think we know and what we know that we don’t know. Bone 49:56–65. https://doi.org/10.1016/j.bone.2010.10.159
Hoefert S, Schmitz I, Tannapfel A, Eufinger H (2010) Importance of microcracks in etiology of bisphosphonate-related osteonecrosis of the jaw: a possible pathogenetic model of symptomatic and non-symptomatic osteonecrosis of the jaw based on scanning electron microscopy findings. Clin Oral Investig 14:271–284. https://doi.org/10.1007/s00784-009-0300-6
Kim JW, Landayan MEA, Lee JY, Tatad JCI, Kim SJ, Kim MR, Cha IH (2016) Role of microcracks in the pathogenesis of bisphosphonate-related osteonecrosis of the jaw. Clin Oral Investig 20:2251–2258. https://doi.org/10.1007/s00784-016-1718-2
Taguchi A, Uemura Y, Imai T et al (2019) Incidence of osteonecrosis of the jaw in Japanese osteoporosis patients taking minodronic acid. J Bone Miner Metab 37:886–892. https://doi.org/10.1007/s00774-019-00990-5
Chiu WY, Yang WS, Chien JY, Lee JJ, Tsai KS (2018) The influence of alendronate and tooth extraction on the incidence of osteonecrosis of the jaw among osteoporotic subjects. PLoS One 13:1–12. https://doi.org/10.1371/journal.pone.0196419
Kos M, Junka A, Smutnicka D, Bartoszewicz M, Kurzynowski T, Gluza K (2013) Pamidronate enhances bacterial adhesion to bone hydroxyapatite. Another puzzle in the pathology of bisphosphonate-related osteonecrosis of the jaw? J Oral Maxillofac Surg 71:1010–1016. https://doi.org/10.1016/j.joms.2012.12.005
Boff RC, Salum FG, Figueiredo MA, Cherubini K (2014) Important aspects regarding the role of microorganisms in bisphosphonate-related osteonecrosis of the jaws. Arch Oral Biol 59:790–799. https://doi.org/10.1016/j.archoralbio.2014.05.002
Schipmann S, Metzler P, Rössle M, Zemann W, von Jackowski J, Obwegeser JA, Grätz KW, Jacobsen C (2013) Osteopathology associated with bone resorption inhibitors - Which role does Actinomyces play? A presentation of 51 cases with systematic review of the literature. J Oral Pathol Med 42:587–593. https://doi.org/10.1111/jop.12038
Hussein MH, Schneider EK, Elliott AG, Han M, Reyes-Ortega F, Morris F, Blaskovich MAT, Jasim R, Currie B, Mayo M, Baker M, Cooper MA, Li J, Velkov T (2017) From Breast Cancer to Antimicrobial: Combating Extremely Resistant Gram-Negative “superbugs” Using Novel Combinations of Polymyxin B with Selective Estrogen Receptor Modulators. Microb Drug Resist 23:640–650. https://doi.org/10.1089/mdr.2016.0196
Ho Sui SJ, Lo R, Fernandes AR, Caulfield MDG, Lerman JA, Xie L, Bourne PE, Baillie DL, Brinkman FSL (2012) Raloxifene attenuates Pseudomonas aeruginosa pyocyanin production and virulence. Int J Antimicrob Agents 40:246–251. https://doi.org/10.1016/j.ijantimicag.2012.05.009
Conte-Neto N, Bastos A d S, Spolidorio LC, Marcantonio CRA, Marcantonio E Jr (2012) Long-term treatment with alendronate increases the surgical difficulty during simple exodontias - an in vivo observation in Holtzman rats. Head Face Med 8:1. https://doi.org/10.1186/1746-160X-8-20
Richer E, Lewis MA, Odvina CV, Vazquez MA, Smith BJ, Peterson RD, Poindexter JR, Antich PP, Pak CYC (2005) Reduction in normalized bone elasticity following long-term bisphosphonate treatment as measured by ultrasound critical angle reflectometry. Osteoporos Int 16:1384–1392. https://doi.org/10.1007/s00198-005-1848-x
Shahnazari M, Yao W, Dai W et al (2011) Properties in aged rats. Bone 46:1267–1274. https://doi.org/10.1016/j.bone.2009.11.019.Higher
Devlin H, Sloan P (2002) Early bone healing events in the human extraction socket. Int J Oral Maxillofac Surg 31:641–645. https://doi.org/10.1054/ijom.2002.0292
Lv Y, Zhang Z, Su Y, Yuan P, Ma W, Huang W, Xu P (2018) Healing of root and surrounding periodontium after root damage with miniscrew implants: a histomorphologic study in dogs. Clin Oral Investig 22:1103–1111. https://doi.org/10.1007/s00784-017-2194-z
Ema (2014) European Medicines Agency recommends that Protelos / Osseor remain available but with further restrictions. 44:1–3
Grosso A, Douglas I, Hingorani A, MacAllister R, Smeeth L (2008) Post-marketing assessment of the safety of strontium ranelate; a novel case-only approach to the early detection of adverse drug reactions. Br J Clin Pharmacol 66. https://doi.org/10.1111/j.1365-2125.2008.03273.x
NICE (2020) National Institute for Health and Care Excellence. https://www.evidence.nhs.uk/search?q=strontium-ranelate. Accessed 15 Jun 2020
Royal Osteoporosis Society (2019) Strontium ranelate returns to the UK as an osteoporosis drug treatment. In: 04/01/2019. https://theros.org.uk/information-and-support/osteoporosis-treatment/strontium-ranelate/. Accessed 25 May 2020
Ali MS, Berencsi K, Marinier K, Deltour N, Perez-Guthann S, Pedersen L, Rijnbeek P, Lapi F, Simonetti M, Reyes C, Van der Lei J, Sturkenboom M, Prieto-Alhambra D (2020) Comparative cardiovascular safety of strontium ranelate and bisphosphonates: a multi-database study in 5 EU countries by the EU-ADR Alliance. Osteoporos Int. https://doi.org/10.1007/s00198-020-05580-0
Martín-Merino E, Petersen I, Hawley S, Álvarez-Gutierrez A, Khalid S, Llorente-Garcia A, Delmestri A, Javaid MK, Van Staa TP, Judge A, Cooper C, Prieto-Alhambra D (2018) Risk of venous thromboembolism among users of different anti-osteoporosis drugs: a population-based cohort analysis including over 200,000 participants from Spain and the UK. Osteoporos Int 29:467–478. https://doi.org/10.1007/s00198-017-4308-5
Maïmoun L, Brennan TC, Badoud I, Dubois-Ferriere V, Rizzoli R, Ammann P (2010) Strontium ranelate improves implant osseointegration. Bone 46:1436–1441. https://doi.org/10.1016/j.bone.2010.01.379
Karakan NC, Akpınar A, Göze F, Poyraz Ö (2017) Investigating the effects of systemically administered strontium ranelate on alveolar bone loss histomorphometrically and histopathologically on experimental periodontitis in rats. J Periodontol 88:e24–e31. https://doi.org/10.1902/jop.2016.160227
Acknowledgment
We thank Dr. A. Leyva (USA) for English editing of the manuscript. This work was partially funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico—CNPq, Brazil, code 140962/2016-6.
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This work was partially funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico – CNPq, Brazil, code 140962/2016-6.
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Valesca Sander Koth declares that she has no conflict of interest. Fernanda Gonçalves Salum declares that she has no conflict of interest. Maria Antonia Zancanaro de Figueiredo declares that she has no conflict of interest. Karen Cherubini declares that she has no conflict of interest.
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This study was approved by the Ethics Committee on Animals Use of the Pontifical Catholic University of Rio Grande do Sul (PUCRS, protocol #7700). All applicable international, national, and institutional guidelines for the care and use of animals were followed.
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Koth, V.S., Salum, F.G., de Figueiredo, M.A.Z. et al. Morphological and immunohistochemical features of tooth extraction sites in rats treated with alendronate, raloxifene, or strontium ranelate. Clin Oral Invest 25, 2705–2716 (2021). https://doi.org/10.1007/s00784-020-03585-x
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DOI: https://doi.org/10.1007/s00784-020-03585-x