The use of bone morphogenic protein and related therapies in the management of medication-related osteonecrosis of the jaw: a scoping review

Abstract

Medication-related osteonecrosis of the jaw (MRONJ) is an uncommon adverse event of antiresorptive and antiangiogenic medications that can result in severe bony complications. Pentoxifylline and tocopherol (PENTOCO) and bone morphogenic protein (BMP) have shown promise as two therapies that could be effective in the management of MRONJ. The present paper reviews the findings of a total of 12 studies investigating the effectiveness of PENTOCO and BMP in the management of 417 patients with MRONJ. Additionally, three patient cases that were managed at our institution are discussed to supplement the findings of the review. While the available literature on the efficacy of PENTOCO and BMP use in the management of MRONJ is limited, the present study’s findings support the potential effectiveness of these therapies as supplements to medical and surgical interventions currently employed.

Keywords

Medication-related osteonecrosis of the jaw / pentoxifylline / tocopherol / bone-morphogenic protein

References

[1] Marx RE,Ulloa JJ.Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment.J Oral Maxillofac Surg2007;65:2397-410

[2] Ruggiero SL, Dodson TB, Fantasia J, et al; American Association of Oral and Maxillofacial Surgeons. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw-2014 update. J Oral Maxillofac Surg. 2014;72:1938-56.

[3] Russell RG.Bisphosphonates: mode of action and pharmacology.Pediatrics2007;119:S150-62

[4] Rogers MJ,Munoz MA.Molecular mechanisms of action of bisphosphonates and new insights into their effects outside the skeleton.Bone2020;139:115493

[5] Matsumoto T.RANKL as a target for the treatment of osteoporosis.J Bone Miner Metab2021;39:91-105

[6] Tetradis S,Ruggiero SL.Pathophysiology of medication-related osteonecrosis of the jaw-a minireview.JBMR Plus2023;7:e10785 PMCID:PMC10443081

[7] Ruggiero SL,Carlson E.Bisphosphonate-related osteonecrosis of the jaw: background and guidelines for diagnosis, staging and management.Oral Surg Oral Med Oral Pathol Oral Radiol Endod2006;102:433-41

[8] Heifetz-Li JJ,Campbell CB,Fielding AF.Systematic review of the use of pentoxifylline and tocopherol for the treatment of medication-related osteonecrosis of the jaw.Oral Surg Oral Med Oral Pathol Oral Radiol2019;128:491-7.e2

[9] Kim KM,Hwang H.Effects of daily versus weekly teriparatide for medication-related osteonecrosis of the jaw: a case-control study.Oral Dis2024;30:3286-95

[10] Katagiri T.Bone morphogenetic proteins.Cold Spring Harb Perspect Biol2016;8:a021899 PMCID:PMC4888821

[11] Ruppert R,Sebald W.Human bone morphogenetic protein 2 contains a heparin-binding site which modifies its biological activity.Eur J Biochem1996;237:295-302

[12] Irie A,Kimata K.Heparan sulfate is required for bone morphogenetic protein-7 signaling.Biochem Biophys Res Commun2003;308:858-65

[13] Takada T,Ifuku M.Sulfated polysaccharides enhance the biological activities of bone morphogenetic proteins.J Biol Chem2003;278:43229-35

[14] Tricco AC,Zarin W.PRISMA extension for scoping reviews (PRISMA-ScR): checklist and explanation.Ann Intern Med2018;169:467-73

[15] Arksey H.Scoping studies: towards a methodological framework.Int J Soc Res Methodol2005;8:19-32

[16] Durieux N,Pasleau F.[OCEBM levels of evidence system].Rev Med Liege2013;68:644-9

[17] Higgins JP,Chandler J. Cochrane handbook for systematic reviews of interventions version 6.5. Cochrane; 2024. Available from: https://training.cochrane.org/handbook. [Last accessed on 27 Apr 2025].

[18] Colapinto G,Nocini R.Outcomes of a pharmacological protocol with pentoxifylline and tocopherol for the management of medication-related osteonecrosis of the jaws (MRONJ): a randomized study on 202 osteoporosis patients.J Clin Med2023;12:4662 PMCID:PMC10380687

[19] Fernandes TL,Franco GCN.Treatment of medication-related osteonecrosis of the jaws without segmental resections: a case series.Am J Case Rep2024;25:e942980 PMCID:PMC10910867

[20] Magalhães JMI, da Motta Silveira FM, Regueira LS, de Lima E Silva DF, de Andrade Veras SR, de Mello MJG. Pentoxifylline and tocopherol as prophylaxis for osteonecrosis of the jaw due to bone-modifying agents in patients with cancer submitted to tooth extraction: a case series. Support Care Cancer. 2023;31:462.

[21] Martin K,Bunyan R.Medication related osteonecrosis of the jaw: an adjunctive medical regime.Oral Surgery2018;11:266-72

[22] Owosho AA,Huryn JM.Pentoxifylline and tocopherol in the management of cancer patients with medication-related osteonecrosis of the jaw: an observational retrospective study of initial case series.Oral Surg Oral Med Oral Pathol Oral Radiol2016;122:455-9 PMCID:PMC5454806

[23] Słowik Ł,Nowak A,Okła M.Pharmacological treatment of medication-related osteonecrosis of the jaw (MRONJ) with pentoxifylline and tocopherol.J Clin Med2025;14:974 PMCID:PMC11818125

[24] Varoni EM,Villa G,Sardella A.Conservative management of medication-related osteonecrosis of the jaws (MRONJ): a retrospective cohort study.Antibiotics2021;10:195 PMCID:PMC7922963

[25] Jung J,Kim GT.Short-term teriparatide and recombinant human bone morphogenetic protein-2 for regenerative approach to medication-related osteonecrosis of the jaw: a preliminary study.J Bone Miner Res2017;32:2445-52

[26] Kim MS,Kim BJ,Kim JH.Immediate reconstruction of mandibular defect after treatment of medication-related osteonecrosis of the jaw (MRONJ) with rhBMP-2/ACS and miniplate: review of 3 cases.Int J Surg Case Rep2020;66:25-9 PMCID:PMC6909046

[27] Park JH,Kim SJ.Does the addition of bone morphogenetic protein 2 to platelet-rich fibrin improve healing after treatment for medication-related osteonecrosis of the jaw?.J Oral Maxillofac Surg2017;75:1176-84

[28] Rahim I,Heliotis M.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 Surg2015;53:870-4

[29] Sterne JA,Reeves BC.ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions.BMJ2016;355:i4919 PMCID:PMC5062054

[30] Srivastava A,Geng Y.Prevalence of medication related osteonecrosis of the jaw in patients treated with sequential antiresorptive drugs: systematic review and meta-analysis.Support Care Cancer2021;29:2305-17 PMCID:PMC12010772

[31] Sultan A,Margalit DN.The use of hyperbaric oxygen for the prevention and management of osteoradionecrosis of the jaw: a Dana-Farber/Brigham and women’s cancer center multidisciplinary guideline.Oncologist2017;22:343-50 PMCID:PMC5344641

[32] Grisar K,Schoenaers J.Osteoradionecrosis and medication-related osteonecrosis of the jaw: similarities and differences.Int J Oral Maxillofac Surg2016;45:1592-9

[33] Li Z,Huang X,Zhang L.Oral microbiota may affect osteoradionecrosis following radiotherapy for head and neck cancer.J Transl Med2023;21:391 PMCID:PMC10276415

[34] Choi NR,Han H,Kim YD.Next-generation sequencing analysis of bacterial species present in the sequestrum of medication-related osteonecrosis of the jaw patients.Arch Oral Biol2025;172:106180

[35] Bell DSH.Are the protean effects of pentoxifylline in the therapy of diabetes and its complications still relevant?.Diabetes Ther2021;12:3025-35 PMCID:PMC8586317

[36] Marjanowski SD,Schaller B.[Pentoxifylline and tocopherol - the importance in the treatment of osteoradionecrosis - literature review and case report].Swiss Dent J2021;131:713-8

[37] Broderick C,Abdel-Hadi M.Pentoxifylline for intermittent claudication.Cochrane Database Syst Rev2020;10:CD005262 PMCID:PMC8094235

[38] Martos-Fernández M,López-López J,Balibrea-Del-Castillo JM.Pentoxifylline, tocopherol, and clodronate for the treatment of mandibular osteoradionecrosis: a systematic review.Oral Surg Oral Med Oral Pathol Oral Radiol2018;125:431-9

[39] Cavalcante RC.Pentoxifylline and tocopherol protocol to treat medication-related osteonecrosis of the jaw: a systematic literature review.J Craniomaxillofac Surg2020;48:1080-6

[40] Lyons AJ.Pentoxifylline - a review of its use in osteoradionecrosis.Br J Oral Maxillofac Surg2017;55:230-4

[41] Peng WX.Adenovirus-mediated expression of BMP-2 and BFGF in bone marrow mesenchymal stem cells combined with demineralized bone matrix for repair of femoral head osteonecrosis in beagle dogs.Cell Physiol Biochem2017;43:1648-62

[42] Bian Y,Lv Z.Bone tissue engineering for treating osteonecrosis of the femoral head.Exploration2023;3:20210105 PMCID:PMC10190954

[43] Zhu H,Cai X,Zhou C.The combination of PLLA/PLGA/PCL composite scaffolds integrated with BMP-2-loaded microspheres and low-intensity pulsed ultrasound alleviates steroid-induced osteonecrosis of the femoral head.Exp Ther Med2020;20:126 PMCID:PMC7523288

[44] Beederman M,Nan G.BMP signaling in mesenchymal stem cell differentiation and bone formation.J Biomed Sci Eng2013;6:32-52 PMCID:PMC4725591

[45] Wu Z,Zhou S.The synergetic effect of bioactive molecule-loaded electrospun core-shell fibres for reconstruction of critical-sized calvarial bone defect-the effect of synergetic release on bone formation.Cell Prolif2020;53:e12796 PMCID:PMC7162799

[46] Jilka RL.Molecular and cellular mechanisms of the anabolic effect of intermittent PTH.Bone2007;40:1434-46 PMCID:PMC1995599

[47] Neer RM,Zanchetta JR.Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis.N Engl J Med2001;344:1434-41

[48] Brixen KT,Ejersted C.Teriparatide (biosynthetic human parathyroid hormone 1-34): a new paradigm in the treatment of osteoporosis.Basic Clin Pharmacol Toxicol2004;94:260-70

[49] Sim IW,Tsao C.Teriparatide promotes bone healing in medication-related osteonecrosis of the jaw: a placebo-controlled, randomized trial.J Clin Oncol2020;38:2971-80