Bisphosphonates: types, mechanisms of action and side effects. Literature review for guidance of professionals and students from medical and dental sciences
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Abstract
Antiresorptive are potent inhibitors of bone resorption widely used in the treatment of osteoporosis and bone metabolism diseases associated or not with neoplasias. Due to their efficacy, anti-resorptives such as bisphosphonates (BPs) are largely prescribed. However, these medications have been associated with several side effects, such as, Medication Related Osteonecrosis of the Jaws (MRONJ). In a literature review, we observed a lack of knowledge by health professionals, regarding this pathology. Considering these data, this current review aims to provide these professionals, especially physicians and dental surgeons, a better understanding of the BPs, their types, mechanisms of action in the bone tissue and metabolism, possible side effects, especially BRONJ, methods for its prevention and treatment. In addition, data regarding knowledge of physicians, dental surgeons and patients about BPs were also collected. To carry out the bibliographic survey, Pubmed, Scieloand Google Academic databases were used and articles published from 1981 to 2022 were selected. From the literature data, it can be concluded that BPs reduce bone resorption mainly by directly inhibiting osteoclasts. Despite its effectiveness in the treatment of bone pathologies, BPs can lead to alterations in the gastrointestinal tract, renal toxicity, alterations in the eye region, and bone osteonecrosis, especially the MRONJ. The knowledge of the MRONJ by health professionals is still restricted, and this seems to be associated with a deficiency in the instruction of the users of the BPs, regarding the problem. Even in the face of several treatment types proposed in the literature, MRONJ still presents difficult resolution. Therefore, its prevention is extremely relevant. In order to prevent it, the interaction between doctors, dentists and patients needs to be better established. In this paper, besides guidelines for dentists, physicians and students from these areas, techniques to mitigatin the risk and to treat MRONJ are proposed for dentists.
KEYWORDS: bisphosphonates; knowledge; bone resorption; osteoclast; osteonecrosis of the jaws.
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References
ABRAHAMSEN, B. adverse effects of bisphosphonates. Calcifed tissue international, v.86, n.6, p.421-35, 2010.
ALHUSSAIN, A.; PEEL, S.; DEMPSTER, L.; CLOKIE, C.; AZARPAZHOOH. Knowledge, practices, and opinions of ontario dentists when treating patients receiving bisphosphonates. Journal of Oral Maxiilofacial Surgery, v.73, n.6, p.1095-105, 2015.
AL-MAWERI, SA; ALSHAMMARI, MN; ALHARBI, AR; BAHEIN, AA; ALHAJJ, MN; AL-SHAMIRI, HM; ALAHMARY, AW; DOUMANI, M. Knowledge and opinion of Saudi dentists regarding dental treatment of patients undergoing bisphosphonates. European Journal of Dentistry, v.14, n.1, p.144-51, 2020.
AL-SAMMAN, AA; AL-ANI, R; A cross-sectional survey on medication-related osteonecrosis of the jaws' knowledge and awareness in a sample of dental society. Journal of Cranio- Maxillofacial Surgery, v.47, n.6, p.926-31, 2019.
AMIN, D; CORNELL, SA; BILDER, GE. 1-Hydroxy-3- (methylpentylamino)-propylidene-1,1-bisphosphonic acid as a potent inhibitor of squalene synthase. Arzneimittel Forschung, v.46, n.8, p.759-62, 1996.
ARANA-CHAVEZ, V; BRADACHIA-CORREA, V. Biologia celular e tecidual para odontologia: moléculas, células e tecidos. Rio de Janeiro: Guanabara Koogan, 2012., p.328, 1. ed.
ASAGIRI, M; TAKAYNAGI, H. The molecular understanding of osteoclast differentiation. Bone, v.40, n.2, p.251-64, 2007.
BAR-SHAVIT, Z. Taking a toll on the bones: regulation of bone metabolism by innate immune regulators. Autoimmunity, v.41, n.3, p.195-203, 2008.
BAUER, JS; BECK, N; KIEFER, J; STOCHMANN, P; WICHMANN, M.; EITNER, S. Awareness and education of patients receiving bisphosphonates. Journal of Cranio- Maxillofacial Surgery, v.40, n.3, p.277-82, 2012.
BORTOLINI, MP. Bifosfonatos na odontologia. 2009. p.41. (Odontologia) – Universidade de Tuiuti do Paraná.
BOYCE, BF; YAO, Z; XING, L. Osteoclasts have multiple roles in bone in addition to bone resorption. Critical Reviews in Eukaryotic Gene Expression, v.19, n.3, p.171-80, 2009.
BROZOSKI, MA; TRAINA, AA; DEBONI, MCZ; MARQUES, MM; NACLÉRIO-HOMEM, MG. Osteonecrose maxilar associada ao uso de bisfosfonatos. Revista Brasileira de Reumatologia, v.52, n.2, p.260-270, 2012.
BRUCKMOSER, E; PALAORO, M; LATZKO, L; SCHNABI, D; NEURURER, SB; JOHANNES, L. Choosing the right partner for medication related osteonecrosis of the jaw: what Central European dentists know. Internacional Journal of Environmental Research and Public Health, v.18, n.9, p.4466, 2021.
BYRNE, PV; GUILBERT, LJ; STANLEY, ER. Distribution of cells bearing receptors for a colony-stimulating factor (CSF-1) in murine tissues. Journal of Cell Biology, v.91, p.848-53, 1981.
CAMPISI, G; MAUCERI, R; BERTOLDO, F; BETTINI, G; BIASOTTO, M; COLELLA, G; CONSOLO, U; FEDE, O; FAVIA, G; FUSCO, V; GABRIELE, M; CASTRO, A; MUZIO, L; MARCIANO, A; MASCITTI, M; MELETI, M; MIGNOGNA, MD; OTERI, G; PANZARELLA, V; UMBERTO, R; ANDREA, S; VESCOVI, P; MARCHETTI, C; BEDOGNI. Medication- related osteonecrosis of jaws (MRONJ) prevention and diagnosis: Italian Consensus Update 2020. Internacional Journal of Environmental Research and Public Health, v.17, n.16, 2020.
CASTRO, LFC; SILVA, ATA; CHUNG, MC. Bifosfonatos (BPs) como transportadores. osteotrópicos no planejamento de fármacos dirigidos. Quimíca Nova, v.27, n.3, p.456-460, 2004.
CHAVES, RAC; ORFÃO, AMA; JUNIOR, WB; QUEIROZ, TP; FALONI, AP. Bifosfonatos e denosumabes: mecanismos de ação e algumas implicações para a implantodontia. Revista Brasileira Multidisciplinar, v.21, n.2, p.66-80, 2018.
CUMMINGS, SR; MARTIN, JS; MCCLUNG, MR; SIRIS, ES. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. New England Journal of Medicine, v.361, n 8, p.756-65, 2009.
DE SOUZA FALONI, AP; SCHOENMAKER, T; AZARI, A; KATCHBURIAN; CERRI, PS; VRIES, TJV; EVERTS, V. Jaw and long bone marrows have a different osteoclastogenic potential. Calcified Tissue International, v.88, n.1, p.63-74, 2011.
DIEL, IJ; BERGNER, R; GROT, KA. Adverse effects of bisphosphonates: current issues. The Journal of Supportive Oncology, v.5, n.10, p. 475-82, 2007.
DOTTO M. L; DOTTO, AC. Osteonecrose dos maxilares induzida por bisfosfonatos – revisão de literatura e relato de caso. Revista da Faculdade de Odontologia, v.16, n.2, p.229-233, 2011.
ESCOBEDO, MP; GARCIA-CONSURGRA, L; GAY, S; ALVAREZ, L; OLAY, S; ASCANI, G; JUNQUERA, L. Influence of the teaching program on the learning in knowledge and practice of osteonecrosis of the jaws produced by antireasorptives in dental students of the Principality of Asturias (Spain). Journal of Clinical and Experimental Dentistry, v.9, n.12, p. 1202-7, 2017.
FACCIO, R; TAKESHITA, S; ZALLONE, A; ROSS, FP; TEITELBAUM, SL. C-Fms and the αvβ3 integrin collaborate during osteoclast differentiation. Journal of Clinical Investigation, v.111, n.5, p.749-58, 2003.
FERREIRA-JUNIOR, CD; CASADO, PL; BARBOZA, ESP. Osteonecrose associada aos bifosfonatos na odontologia. Revista Periodontia, v.17, n.4, p.24-30, 2007.
FIZAZI, K; CARDUCCI, M; SMITH, M; DAMIÃO, R; BROWN, J; KARSH, L; MILECKI, P; NEAL, C; RADER, M; WANG, H; JIANG, Q; TADROS, S; DANSEY, R; GOESSL, C. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomized, double-blind study. The Lancet, v.377, n.9768, p.813-22, 2011.
GIOVANNACCI, I; MELETI, M; MANFREDI, M; MORTELLARO, C; LUCCHINA, AG; BONANINI, M; VESCOVI, P. Medication- related osteonecrosis of the jaw around dental implants: implant surgery- triggered or implant presence- triggered osteonecrosis? Journal of Craniofacial Surgery, v.27, n.3, p.697-701, 2016.
GOVAERTS, D; PICCART, F; OCKMERMAN, A; COROPCIUC, R; POLITIS, C; JACOBS, R. Adjuvant therapies for MRONJ: A systematic review. Bone, v.141, 2020.
GREEN, J; CLÉZARDIN, P. Mechanism of biphosphonate effects on osteoclast, tumor cell growth and metastasis. American Journal of Clinical Oncology, v.25, n.6, p.53-59, 2002.
HERNANDEZ S. V; JANÉ-SALA, E; PÉRES, RT; LÓPEZ-LÓPES, J. Osteonecrosis de maxilares asociada al uso de bifosfonatos: Revisión de 491 casos. Avances en odontoestomatologia, v.28, n. 4, p.199- 209, 2012.
HOGAN, PG; CHEN, L; NARDONE, J; RAO, A. Transcriptional regulation by calcium, calcineurin and NFAT. Genes & Development, v.17, n.18, p.2205-32, 2003.
KIMMEL, D. Mechanism of action, pharmacokinetic and pharmacodynamic profile, and clinical applications of nitrogen-containing bisphosphonates. Journal of dental research, v.86, n.11, p.1022-33, 2007.
KIM, J. H; KIM, N. Regulation of NFATc1 in Osteoclast Differentiation. Journal of Bone Metabolism, v.21, n.4, p.233-41, 2014.
KUN-DARBOIS, JD; FAUVEL, F; Medication- related osteonecrosis and osteoradionecrosis of the jaws: uptade and current management. Morphologie, v.105, n.349, p.170-87, 2021.
MARTINS, AS; CORREIA, JA; SALVADO, F; CALDAS, C; SANTOS, N; CAPELO, A; PALMELA, P. Relevant factors for treatment outcome and time to healing in medication- related osteonecrosis of the jaws- a retrospective cohort study. Journal of Cranio-Maxillofacial Surgery, v.45, n.10, p.1736-42, 2017.
MIZUKAMI, J; TAKAESU, G; AKATSUKA, H; SAKURAI, H; NINOMIYA-TSUJI, J; MATSUMOTO, K; SAKURAI, K. Receptor activador of NFkB ligand (RANK-L) activates TAK1 mitogen- activated protein kinase through a signaling complex containing RANK, TAB2 and TRAF6. Molecular and Cellular Biology, v.22, n.4, p.992-1000, 2002.
MONKKONEN, H; AURIOLA, S; LEHENKARI, P; KELLINSALMI, M; HASSINEN, IE; VEPSALAINEN, J; MONKKONEN, J. A new endogenous ATP analog (Apppl) inhibits the mitochondrial adenine nucleotide translocase (ANT) and is responsible for the apoptosis induced by nitrogen- containing bisphosphonates. British Journal of Pharmacology, v.147, n.4, p.437-45, 2006.
MOURÃO, CFAB; MOURA, AP; MANSO, JEF. Tratamento da osteonecrose dos maxilares associada aos bifosfonatos: revisão da literatura. Revista Brasileira de Cirurgia da Cabeça e Pescoço, v.42, n.2, p.113-117, 2013.
NANCOLLAS, GH; TANG, R; PHIPPS, RJ; HENNEMAN, Z; GULDE, S; WU,W; MANGOOD, U; RUSSEL, RGG; EBETINO, FH. Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone, v. 38, n.5, p.617-27, 2004.
NUNES, V; LOPES, B; LORDANI, RXF; ALVES, J; ROCHA, R; MACHADO, W; OLIVEIRA, L CBS. Uso de bifosfonatos em pacientes com câncer e sua associação com osteonecrose dos ossos maxilares – uma revisão de literatura. Revista Periodontia, v.20, n.3, 2010.
OSTA, LE; OSTA, BE; LAKIS, S; HENNEQUIN, M; OSTA, NE. Bisphosphonate-related osteonecrosis of the jaw: awareness and level of knowledge of Lebanese physicians. Supportive Care in Cancer, v.23, n.9, p.2825-31, 2015.
OTOMO-CORGEL, J. Osteoporosis and osteopenia: implications for periodontal and implant therapy. Periodontology 2000, v.59, n.1, p.111–39, 2012.
PAPAPETROU, PD. Bisphosphonate-associated adverse events. Hormones, v.8, n.2, p.96-110, 2009.
PASSERI, LA; BÉRTOLO, MB; ABUABARA, A. Osteonecrose dos maxilares associada ao uso de bisfosfonatos. Revista Brasileira de Reumatologia, v.51, n.4, p.401-7, 2011.
PAZ, FJS; PAIVA, THS; BARBOSA, KGN. Osteonecrose dos maxilares associada ao uso de bifosfonatos: uma revisão de literatura. Clínica e Pesquisa em Odontologia, v.6, n.1, p.59-68, 2014.
PINTO, VMC. Osteonecrose da mandíbula e/ou maxilas em pacientes submetidos à terapia com bisfosfonatos. 2010. p.49. Pós-Graduação em Ciências (Oncologia)- Fundação Antônio Prudente, São Paulo, 2010.
PLOTKIN, L; MANOLAGAS, SC; BELLIDO, T. Dissociation of the pro-apoptotic effects of bisphosphonates on osteoclasts from their anti-apoptotic effects on osteoblasts/osteocytes with novel analogs. Bone, v.39, n.3, p.443-52, 2006.
RANG, H. P. Farmacologia. 7. ed. Rio de Janeiro: Ed. Elsevier, 2012.
RAZAVI, V; JAFARI, A; VESCOVI, P; FEKRARAD, R. Efficacy of adjunctive photobiomodulation management of medication- related osteonecrosis of the jaw: a systematic review. Photomedicine and Laser Surgery, v.40, n.12, p.777-91, 2022.
REID, IR. Efficacy, effectiveness and side effects of medications used to prevent fractures. Journal of Internal Medicine, v.277, n.6, p.690-706, 2015.
ROGERS, M.J; GORDON, S; BENFORD, HL; COXON, FP; LUCKMAN, SP; MONKKONEN, J; FRITH, JC. Cellular and Molecular Mechanisms of Action of Bisphosphonates. Cancer Supplement, v.88, n.12, p.2961-78, 2000.
ROGERS, MJ; JI, X; RUSSEL, RG; BLACKBURN, G M; WILLIAMSON, MP; BAYLESS, AV; EBETINO, FH; WATTS, DJ. Incorporation of bisphosphonates into adenine nucleotides by amoebae of the cellular slime mould dictyostelium discoideum. Biochemical Journal, v.303, n.1, p.303-11, 1994.
ROTH, P; STANLEY, ER. The biology of CSF-1 and its receptor. Current topics in microbiology and immunology, v.181, n.1, p.141-67, 1992.
RUGGIERO, SL; DODSON, TB; AGHALOO, T; CARLSON, RR; WARD, BB; KADEMANI, D. American Association of Oral and Maxillofacial Surgeons’ Position Paper on Medication-Related Osteonecrosis of the Jaws—2022 Update. Journal of Oral and Maxillofacial Surgery, v.80, n.5, p.920-43, 2022.
RUGGIERO, SL; DODSON, TB; ASSAEL, LA; LANDESBERG, R; MARX, RE; MEHROTRA, B. American Association of Oral and Maxillofacial Surgeons’ Position Paper on Medication-Related Osteonecrosis of the Jaws-2009 Update. Journal of Oral and Maxillofacial Surgery, v.67 n.5, p.2-12, 2009.
RUGGIERO, SL; DODSON, TB; FANTASIA, J; BOMDIA, R; AGHALOO, T; MEHROTRA, B; O’RYAN, F. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw-2014 update. Journal of Oral and Maxillofacial Surgery, v.72, n.10, p.1938-56, 2014.
RUOCCO-VETUCCI, V; FALONI, APS; FAEDA, RS. Up of an Implant Supported Rehabilitation After Long-Term Use of Alendronate. The Journal of Craniofacial Surgery, v.30, n.8, p.793-6, 2019.
RUSSMUELLER, G; SEEMANN, R; WEISS, K; STADLER, V; SPEISS, M; PERISANIDIS, C; FUEREDER, T; WILLINGER, B; SULZBACHER, I; STEININGER, C. The association of medication- related osteonecrosis of the with Actinomyces spp. Infection. Scientific Reports, v.17, n.6, 2016.
SAFRIADI, F. Bone metastases and bone loss medical treatment in prostate cancer patients. Acta medica Indonesiana, v.45, n.1, 2013.
SENTÜRK, FM.; CIMEN, E; ÖNCÜL, TMA; CAMBAZOGLU, M. Oncologists awareness about bisphosphonate related osteonecrosis of the jaws. Journal of Pakistan Medical Association, v.66, n.7, p.880-3, 2016.
SOUZA, LN; SOUZA, ACRA; MARI, VFA; BORGES, APN; ALVARENGA, R. Osteonecrose dos Maxilares Associada ao Uso de Bisfosfonatos: Revisão da Literatura e Apresentação de um Caso Clínico. Revista Portuguesa de Estomatologia, Medicina Dentária, e Cirurgia Maxilofacial, v.50, n.4, p.229-36, 2009.
STREWLER, G. Awakened from sleep: dormancy in stem cells and bone metastases. Bone, v.1, p.3-5, 2004.
SUDA, T; TAKAHASHI, N; MARTIN, TJ. Modulation of osteoclast differentiation. Endocrine Reviews, v.13, n.1, p.66–80, 1992.
SUZUKI, K; TAKEYAMA, S; SAKAI, Y; YAMADA, S; SHINODA, H. Current topics in pharmacological research on bone metabolism: inhibitory effects of bisphosphonates on the differentiation and activity of osteoclasts. Journal of pharmacological sciences, v. 100, n.3, p. 189-94, 2006.
TAKAYANAGI, H; KIM, S; KOGA, T; NISHINA, H; ISHIKI, M; YOSHIDA, H; SAIURA, A; ISOBE, M; YOKOCHI, T; INOUSE, J; WAGNER, EF; MAK, TW; KODAMA, T; TANIGUCHI, T. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Developmental Cell, v.3, n.6, p.889-901, 2002.
TARTAROTI, NC; MARQUES, MM; NACLÉRIO-HOMEM, MG; MIGLIORATI, CA; DEBONI, MCZ. Antimicrobial photodynamic and photobiomodulation adjuvante therapies for prevention and treatment of medication- related osteonecrosis of the jaws: case series and long- term follow- up. Photodiagnosis and Photodynamic Therapy, v.29, 2020.
THOMPSON, K; ROGERS, MJ; COXON, FP; CROCKETT, JC. Cytosolic entry of bisphosphonate drugs requires acidification of vesicles after fluid-phase endocytosis. Molecular Pharmacology, v.69, n.5, p.1624-32, 2006.
TUSHINSKI, RJ; OLIVER, IT; GUILBERT, LJ; TYNAN, PW; WARNER, JR; STANLEY, ER. Survival of mononuclear phagocytes depends on a lineage- specific growth factor that the differentiated cells selectively destroy. Cell Press, v.28, n.1, p.71-81, 1982.
UYANNE, J; CALHOUN, CC; LE, AD. Antiresorptive drug- related osteonecrosis of the jaw.Dental Clinics of North America, v.58, n.2, p.369-84, 2013.
WOOLFORD, J; ROTHWELL, V; ROHRSCHNEIDER, L. Characterization of the human c-fms gene product and its expression in cells of the monocyte–macrophage lineage. Molecular and Cellular Biology, v.5, n.12, p.3458–3466, 1985.
YAGI, M; MIYAMOTO, T; SAWATANI, Y; IWAMOTO, K; HOSOGANE, N; FUJITA, N; MORITA, K; NINOMIYA, K; SUZUKI, T; MIYAMOTO, K; OIKE, Y; TAKEYA, M; TOYAMA, Y; SUDA, T. DC-STAMP is essential for cell in osteoclast and foreign body giantcells. Journal of Experimental Medicine, v.202, n.3, p.345–51, 2002.
YONEDA, T; HAGINO, H; SUGIMOTO, T; OHTA, H; TAKAHASHI, S; SOEN, S; TAGUCHI, A; NAGATA, T; URADE, M; SHIBAHARA, T; TOYOSAWA, S. Antiresorptive agente- related osteonecrosis of the jaw: Position paper 2017 of the Japanese allied committee on osteonecrosis of the jaw. Journal of bone and mineral metabolism, v.35, n.1, p.6-19, 2017.