|Year : 2019 | Volume
| Issue : 5 | Page : 487-492
The long-term risks and complications of bovine-derived xenografts: A case series
Angel Emmanuel Rodriguez, Hessam Nowzari
Private Practice, Beverly Hills, California, USA
|Date of Submission||30-Oct-2018|
|Date of Acceptance||31-Jan-2019|
|Date of Web Publication||29-Aug-2019|
Dr. Angel Emmanuel Rodriguez
120 South Spalding Drive, Suite 201, Beverly Hills, CA 90212
Source of Support: None, Conflict of Interest: None
| Abstract|| |
The frequency of dental implant related surgeries that involve soft tissue and bone augmentation procedures has increased significantly. Bovine-derived substitutes have been by far the most commonly used xenografts in dentistry. Albeit literature is replete with clinical studies in favor of bovine-derived graft materials, bibliographical data reporting on risks and clinical complications is scarce. Clinical impression and concern for patient safety led to the report we have provided. The aim of the present case series was to raise awareness on the long-term risks and late clinical complications of bovine-derived graft materials. Patients were referred to a private practice due to bone augmentation complications. Demographics, significant medical and dental findings are reported. Complications included sinus and maxillary bone pathoses, displacement of the graft materials, oroantral communications, implant failure, foreign body reactions, encapsulation, chronic inflammation, soft tissue fenestrations and associated cysts. Bovine-derived graft materials were not biodegradable. Resolution of the associated lesions and symptoms was achieved after the removal of the bone graft materials. The surgical removal of the xenograft materials may require advanced clinical skills because of the different configurations clinicians might encounter of the non-resorbed and migrated particles. The authors' concern is that patient morbidity may not be reduced with xenografts, due to the inherent risks and associated complications. Clinicians seeking to provide functional and esthetic outcomes should be aware of the complications of the bovine-derived graft materials. The long-term safety of xenografts and their potential association with disease are valid concerns.
Keywords: Anorganic bovine bone substitutes, bone transplantation, bovine-derived graft, complications, dental implant, maxillary sinus, xenograft
|How to cite this article:|
Rodriguez AE, Nowzari H. The long-term risks and complications of bovine-derived xenografts: A case series. J Indian Soc Periodontol 2019;23:487-92
|How to cite this URL:|
Rodriguez AE, Nowzari H. The long-term risks and complications of bovine-derived xenografts: A case series. J Indian Soc Periodontol [serial online] 2019 [cited 2020 Feb 21];23:487-92. Available from: http://www.jisponline.com/text.asp?2019/23/5/487/259375
| Introduction|| |
Esthetics is an inseparable part of today's dental treatment; however, consistency of results, reliability of treatment modalities, and long-term prognosis require scientific approaches to therapeutic procedures. The optimal dental solution recognizes the long-term well-being of the patient. All treatment planning must have proven scientific basis that will predict what lies ahead for the patient in years to come.
The frequency of dental implant-related surgeries that involve soft-tissue and bone augmentation surgical procedures has increased significantly. Bovine-derived substitutes are by far the most commonly used xenograft in dentistry.,, However, bibliographical data reporting on clinical complications are scarce and the long-term safety is rarely addressed in dental literature; the risk of bovine spongiform encephalopathy (BSE). Reported complications have included as follows: acute and chronic sinusitis, maxillary fungus ball, material displacement, immune reactions, chronic inflammation, foreign body reaction,,,,, and the risk of disease transmission (variant Creutzfeldt–Jakob disease).,
Dental literature is replete with clinical studies in favor of anorganic bovine bone as grafting material. Nevertheless, a close evaluation of published papers in favor of bovine-derived graft materials reveals wide variation in the study designs, creating conditions for erroneous conclusions from the methods used. Often, the use of broad or vague definitions and errors in analytical models can be noted. Recently, Kim et al. concluded that the long latency period to manifestation of the disease (1 to over 50 years) in xenograft-infected patients provides a framework for discussing possible long-term risks of the xenografts.
The purpose of the present case series was to raise awareness on the long-term risks and late complications of bovine-derived xenografts. Concern for patients led to the report we have provided. Without anticipating potential failure, any immediate success is limited to initial satisfaction and ignores the far greater elements of the problematic outcome yet to occur.
| Case Reports|| |
All patients were provided with the written informed consent and the Health Insurance Portability and Accountability Act documents. Identity of the patient and health-care providers have been excluded from the study. Primary ethical approval was obtained by the competent local authority. Patients were referred to a private practice due to bone augmentation complications. Patients' demographic, significant medical and dental findings are reported. The following descriptions are the overviews of the affected patients.
Patient 1 was a 60-year-old female with no significant medical history. Approximately 2 years before her visit, the left lateral incisor extraction site was xenografted. Clinical evaluation revealed localized soft-tissue inflammation associated with edema and pain. At palpation, a mobile mass could be detected. Surgical exposure revealed a mass of encapsulated xenograft particles that was removed. Treatment consisted of autogenous bone augmentation and soft-tissue grafting [Figure 1].
|Figure 1: Clinical photography from the baseline to final result (a-c). Notice the chronic inflammation, edema, and gingival fenestration (arrow) caused by bovine-derived bone particles at baseline (a). Resolution of gingival fenestration and chronic inflammation after removal of bovine-derived biomaterials (c). Periapical radiograph (d). Surgical removal of the encapsulated bovine-derived biomaterials (e-h). Autogenous bone blocks graft surgery (i). Implant placement (j and k). Autogenous connective tissue graft (l). Periapical radiograph at 5-year follow-up (m)|
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Patient 2 was a 52-year-old female with no significant medical history. The full edentulous maxilla was restored with nine dental implants following bone augmentation procedures. Five years after what was considered to be a successful treatment, facial edema was associated with pain and discomfort, migrating bovine bone particles and peri-implantitis. After the removal of the bovine bone particles, pain and edema were eliminated. Subsequently, the implants were removed [Figure 2].
|Figure 2: Smile, frontal, and occlusal photographs (a-c). Surgical removal of bovine-derived bone biomaterials (d-f). Nonresorbed bovine-derived bone particles (g)|
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Patient 3 was a 59-year-old male with a medical history of angina, hypercholesterolemia, aortic valve stenosis, and periodontal disease. Medications included rosuvastatin calcium (40-mg tablet, once daily), nitroglycerin (0.4 mg, sublingual), ticagrelor (90 mg, twice a day), acetylsalicylic acid (81 mg, once every other day), and coenzyme Q10 (300 mg daily). Seven years after bovine bone sinus grafting, the displacement of the graft particles was associated with sinus and maxillary bone pathologies. After surgical debridement, bony defects were repaired using the autogenous bone. Histopathological examinations revealed segments of fibrous and granulation tissue containing a mixed chronic inflammatory cell infiltrates composed of lymphocytes and plasma cells. Occasional macrophages were also seen. Fragments of thin, cystic-type epithelium were noted. The periphery of the cyst walls was compressed and well hyalinized. Large collections of pink amorphous necrotic debris containing cholesterol clefts were detected. No specific microorganism was encountered. No evidence of malignancy was observed in the sections studied [Figure 3].
|Figure 3: Radiographic evaluation of the cystic lesions associated with bovine bone particles (*), scattering of the particles can be observed (a-c). Surgical removal of bovine-derived xenografts (arrow) and associated cyst (d-i)|
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Patient 4 was 87-year-old male with a medical history of hypertension, hypercholesterolemia, osteoarthritis, asthma, and periodontitis. Medications included acetylsalicylic acid (81 mg, once every other day), pravastatin sodium, balsalazide, valsartan, and allopurinol. The patient's otolaryngologist diagnosed him with bovine bone associated left maxillary sinusitis 13 years after sinus elevation. The thickening of the maxillary sinus mucous membrane was detected. The presence of mucoid material had opacified 80% of the sinus. The left nasal fossa including the left middle meatus was also affected and diagnosed with inflammatory/rhinitis. The right ostiomeatal unit areas were clear. The surgical debridement of the maxillary sinus was performed and resulted in significant improvement [Figure 4].
|Figure 4: Misleading periapical radiograph of what was considered to be a successful sinus lift (a). Bovine-derived biomaterial view from the transversal sections of the computed tomography scan (b and c). Frontal sections of computed tomography scan (d-i). Transversal sections of the computed tomography scan (j-o). Notice the opacification (+) of the left maxillary sinus. Note the unhealed access window previously performed for sinus lift procedure (arrow) and the scattered bovine-derived xenograft particles (*)|
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Patient 6 was a 31-year-old female with no medical history. Three years before her visit, the maxillary right lateral incisor was grafted with bovine-derived bone materials followed by implant placement. The migration of the bone particles was associated with the soft-tissue fenestration adjacent to an intact neighboring periodontium. Notably, the change in soft-tissue color and texture associated with the encapsulated bovine bone was observed. Bovine bone particles were removed and autogenous connective tissue grafts were inserted. Gingival fenestration resolved and esthetic outcome was achieved [Figure 5].
|Figure 5: Clinical photographs and periapical radiograph at baseline of the improper dentistry (a-d). Note gingival fenestration associated with bovine-derived biomaterials (c). Surgical removal of bovine-derived bone particles and insertion of connective tissue graft (e). Photography of the achieved esthetic outcome and resolution of gingival fenestration (f). Periapical radiograph at 10-year follow-up (g). Final results (h-i)|
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| Discussion|| |
The long-term safety of xenografts and their potential association with disease transmission are valid concerns. Dental literature has rarely addressed the clinical risks and complications of anorganic bovine bone as a grafting material. However, the scarce literature on complications does not mean that such events are unusual. Often, the “negative” findings are not published or are not being submitted for publication. Ignoring the negative outcomes is worrisome as it skews the scientific literature. “Negative” data can be statistically more trustworthy than positive data. However, regardless of being positive or negative, publication of interesting results would create a more unbiased scientific endeavor. The present report was conceived with the safety of patients in mind.
The major concern of the present report was the late complications extending from 2 to 13 years after what was considered to be a successful treatment outcome. Adverse effects in the present case series report included sinus and maxillary bone pathoses, displacement of the graft materials, oroantral communications, implant failure, foreign body reactions, encapsulation, chronic inflammation, soft-tissue fenestrations, and associated cysts. The bovine bone xenograft is not biodegradable. Mordenfeld et al. provided evidence of deproteinized bovine bone particles not biodegraded after 10 years. Later on, in a human histological and histomorphometrical study, Mordenfeld et al. detected particles of deproteinized bovine bone showing no significant size change at 11 years. Ayna et al. showed the presence of residual bovine bone particles in humans after 14 years. Moreover, Traini et al. reported residual particles of anorganic bovine bone after 20 years in a human clinical and biological performance assessment. In accordance with our observations, foreign body reactions to anorganic bovine bone have also been reported. Histologically, the bovine bone particles have been intimately associated with multinucleated giant cells along with lymphocytes, plasma cells, and histiocytes. The present consecutive case series evidenced encapsulation of the material, clinical signs, and reactions proper of foreign body reactions. The authors' concern is that patient morbidity may not be reduced with xenografts, due to the inherent risks and associated complications.
Although clinicians have interpreted osteoclastic activity around bovine bone particles positively,, it may be of concern to patients' safety as well. Osteoclasts are the only cells capable to degrade the bone matrix by resorption, a required process for bone morphogenesis during development and continual repair of the skeleton (bone remodeling)., The unique specialized attachment to bone matrix is facilitated by integrin receptors such as osteopontin. The detection of osteoclasts in contact with the bovine bone particles and/or allografts  could indicate the presence of proteins in the surface of the “deproteinized” graft particles. Studies have demonstrated the presence of proteins in “anorganic” bovine bone xenografts such as growth factor-β, bone morphogenetic protein, and collagens.,, Interactions of residual proteins within bovine bone particles and the host cell receptors could elicit acute and chronic immune reactions, as well as disease transmission. These findings raise doubt concerning the ability of manufactures to obtain consistently anorganic bovine bone. Bovine bone encephalopathy (BSE) prion inactivation by anorganic bovine bone manufacturing processes has yet to be proven., BSE is a type of transmissible spongiform encephalopathies caused by prion proteins. Prions are well known for their resistance to conventional chemical and physical decontamination methods,, and the heat treatment used for anorganic bovine bone material preparation (300°C for Bio-Oss®, 1100°C for PepGen P-15®) has not proven to inactivate BSE prion. Chronic inflammation of the soft tissue associated with the bovine bone was evidenced in the present report. The inflammatory processes resolved after the removal of the bovine bone materials. The plausibility of bovine-derived bone substitutes in producing immune reactions is present.
Sinusitis, scattering of the graft materials, or wound dehiscence are not unusual when xenografting is performed. Chirilă et al. reported 4.3% occurrence of acute maxillary sinusitis in patients who underwent sinus lift with the use of a combination of xenograft (Cerabone, Botiss biomaterials GmBhH, Gerlingen, Germany or Gen-Os, Osteobiol, Tecnoss Dental, Torino, Italy) and autogenous bone. The clinical signs were headache, locoregional pain, cacosmia, inflammation of the oral buccal mucosa and rhinorrhea, or unilateral nasal discharge. Chronic sinusitis and related symptoms (mucopurulent nasal drainage, facial pain and/or pressure, nasal congestion, and foul smell) have been shown to develop in patients following implant placement and sinus lift. Interestingly, Scolozzi et al. demonstrated association between deproteinized bovine bone (Bio-Oss) substitute and development of fungus ball in the maxillary sinus. Fungus ball represents the most common form of fungal infection involving paranasal sinuses, encountered in 28.5% of patients suffering from chronic maxillary sinusitis. The frequent causative agent is Aspergillus fumigatus. All 13 cases with fungus ball had received anorganic bovine bone. This form of sinusitis typically affects healthy adults. Similar to the present report, resolution or improvement of the symptoms was achieved by removal of the bone graft material.
Sivolella et al. and McCrea  have reported a total of three cases of cysts associated with dental implants. The reported cases developed nasopalatine duct cystic lesions., Cystic lesions associated with bovine bone particles have not been reported in the dental literature. In the present paper, we identified a bovine bone associated cyst 7 years after grafting. The periphery of the cyst wall was well-hyalinized with amorphous necrotic debris.
Autogenous transplants were the treatment of choice for patients that required surgical reconstruction of the tissues after the removal of the xenograft materials. Intraoral soft and hard donor tissue areas share biological, biochemical, and embryological similarities with intraoral recipient sites that enhance transplant vascularization and incorporation. Furthermore, transplants of autogenous origin have a healing and incorporation period shorter when compared to alternatives. Although quantities may be limited, autogenous transplants remained the “gold standard” for the restoration of intraoral tissues volume without immune reactions.,
Dentistry has experienced periods of major excitement followed rapidly by severe disappointments. Ioannidis and Trikalinos provided evidence that the paradoxical events are in part the result of many research teams working in the same field with massive experimental data being produced. Therefore, each team may prioritize pursuing and disseminating its most impressive “positive” results. Frequently, clinicians misled by the overwhelming amount of positive results use vague concepts and conclusions, not clearly substantiated, to develop therapies with disappointing long-term results. The term to describe this phenomenon of rapidly alternating extreme research claims and extremely opposite refutations is known as “Proteus Phenomenon.” “Negative” results are useful and should be disseminated for the science endeavor. Immediate esthetic outcomes are a crucial factor influencing dentistry, which is undeniable of interest to clinicians and patients. However, research and science are about revisiting accepted knowledge, expressing doubt, and positing new questions for consideration. Clinicians seeking to provide functional and esthetic outcomes should be aware of the clinical complications of the bovine-derived graft materials. The surgical removal of the xenograft materials may require advanced clinical skills due to the different configurations clinicians might encounter of the nonresorbed and migrated particles.
| Conclusion|| |
The long-term safety of xenografts and their potential association with disease are valid concerns. The bovine bone xenograft is not biodegradable. Complications in the present case series included sinus and maxillary bone pathologies, displacement of the graft materials, implant failure, foreign body reactions, encapsulation, chronic inflammation, soft-tissue fenestrations, and associated cysts. Resolution or improvement of the associated lesions was achieved by the removal of the bone graft materials. Long-term clinical evaluations are needed to identify the biological complications of xenografts that are used extensively in dentistry.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that names and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Schincaglia GP, Nowzari H. Surgical treatment planning for the single-unit implant in aesthetic areas. Periodontol 2000 2001;27:162-82.
Cha HS, Kim JW, Hwang JH, Ahn KM. Frequency of bone graft in implant surgery. Maxillofac Plast Reconstr Surg 2016;38:19.
Schlegel AK. Bio-oss bone replacement material. Long-term results with bio-oss bone replacement material. Schweiz Monatsschr Zahnmed 1996;106:141-9.
Berglundh T, Lindhe J. Healing around implants placed in bone defects treated with bio-oss. An experimental study in the dog. Clin Oral Implants Res 1997;8:117-24.
Campana V, Milano G, Pagano E, Barba M, Cicione C, Salonna G, et al.
Bone substitutes in orthopaedic surgery: From basic science to clinical practice. J Mater Sci Mater Med 2014;25:2445-61.
Lutz R, Berger-Fink S, Stockmann P, Neukam FW, Schlegel KA. Sinus floor augmentation with autogenous bone vs. A bovine-derived xenograft – A 5-year retrospective study. Clin Oral Implants Res 2015;26:644-8.
Cannizzaro G, Felice P, Leone M, Viola P, Esposito M. Early loading of implants in the atrophic posterior maxilla: Lateral sinus lift with autogenous bone and bio-oss versus crestal mini sinus lift and 8-mm hydroxyapatite-coated implants. A randomised controlled clinical trial. Eur J Oral Implantol 2009;2:25-38.
Bannister SR, Powell CA. Foreign body reaction to anorganic bovine bone and autogenous bone with platelet-rich plasma in guided bone regeneration. J Periodontol 2008;79:1116-20.
Scolozzi P, Perez A, Verdeja R, Courvoisier DS, Lombardi T. Association between maxillary sinus fungus ball and sinus bone grafting with deproteinized bovine bone substitutes: A case-control study. Oral Surg Oral Med Oral Pathol Oral Radiol 2016;121:e143-7.
Jensen T, Schou S, Stavropoulos A, Terheyden H, Holmstrup P. Maxillary sinus floor augmentation with bio-oss or bio-oss mixed with autogenous bone as graft: A systematic review. Clin Oral Implants Res 2012;23:263-73.
Kim Y, Nowzari H, Rich SK. Risk of prion disease transmission through bovine-derived bone substitutes: A systematic review. Clin Implant Dent Relat Res 2013;15:645-53.
Kim Y, Rodriguez AE, Nowzari H. The risk of prion infection through bovine grafting materials. Clin Implant Dent Relat Res 2016;18:1095-102.
Ioannidis JP. Why most published research findings are false. PLoS Med 2005;2:e124.
Mordenfeld A, Albrektsson T, Hallman M. A 10-year clinical and radiographic study of implants placed after maxillary sinus floor augmentation with an 80:20 mixture of deproteinized bovine bone and autogenous bone. Clin Implant Dent Relat Res 2014;16:435-46.
Mordenfeld A, Hallman M, Johansson CB, Albrektsson T. Histological and histomorphometrical analyses of biopsies harvested 11 years after maxillary sinus floor augmentation with deproteinized bovine and autogenous bone. Clin Oral Implants Res 2010;21:961-70.
Ayna M, Açil Y, Gulses A. Fate of a bovine-derived xenograft in maxillary sinus floor elevation after 14 years: Histologic and radiologic analysis. Int J Periodontics Restorative Dent 2015;35:541-7.
Traini T, Piattelli A, Caputi S, Degidi M, Mangano C, Scarano A, et al.
Regeneration of human bone using different bone substitute biomaterials. Clin Implant Dent Relat Res 2015;17:150-62.
Galindo-Moreno P, Hernández-Cortés P, Mesa F, Carranza N, Juodzbalys G, Aguilar M, et al.
Slow resorption of anorganic bovine bone by osteoclasts in maxillary sinus augmentation. Clin Implant Dent Relat Res 2013;15:858-66.
Piattelli M, Favero GA, Scarano A, Orsini G, Piattelli A. Bone reactions to anorganic bovine bone (Bio-oss) used in sinus augmentation procedures: A histologic long-term report of 20 cases in humans. Int J Oral Maxillofac Implants 1999;14:835-40.
Teitelbaum SL. Bone resorption by osteoclasts. Science 2000;289:1504-8.
Charles JF, Aliprantis AO. Osteoclasts: More than 'bone eaters'. Trends Mol Med 2014;20:449-59.
Teitelbaum SL. Osteoclasts: What do they do and how do they do it? Am J Pathol 2007;170:427-35.
Brugnami F, Then PR, Moroi H, Kabani S, Leone CW. GBR in human extraction sockets and ridge defects prior to implant placement: Clinical results and histologic evidence of osteoblastic and osteoclastic activities in DFDBA. Int J Periodontics Restorative Dent 1999;19:259-67.
Schwartz Z, Weesner T, van Dijk S, Cochran DL, Mellonig JT, Lohmann CH, et al.
Ability of deproteinized cancellous bovine bone to induce new bone formation. J Periodontol 2000;71:1258-69.
Tadic D, Epple M. A thorough physicochemical characterisation of 14 calcium phosphate-based bone substitution materials in comparison to natural bone. Biomaterials 2004;25:987-94.
Murugan R, Panduranga Rao K, Sampath Kumar TS. Heat-deproteinated xenogeneic bone from slaughterhouse waste: Physico-chemical properties. Bull Mater Sci 2003;26:523-8.
Brown P. BSE and transmission through blood. Lancet 2000;356:955-6.
Lee J, Kim SY, Hwang KJ, Ju YR, Woo HJ. Prion diseases as transmissible zoonotic diseases. Osong Public Health Res Perspect 2013;4:57-66.
Bartols A, Kasprzyk S, Walther W, Korsch M. Lateral alveolar ridge augmentation with autogenous block grafts fixed at a distance versus resorbable poly-D-L-lactide foil fixed at a distance: A single-blind, randomized, controlled trial. Clin Oral Implants Res 2018;29:843-54.
Chirilă L, Rotaru C, Filipov I, Săndulescu M. Management of acute maxillary sinusitis after sinus bone grafting procedures with simultaneous dental implants placement – A retrospective study. BMC Infect Dis 2016;16 Suppl 1:94.
Jiam NT, Goldberg AN, Murr AH, Pletcher SD. Surgical treatment of chronic rhinosinusitis after sinus lift. Am J Rhinol Allergy 2017;31:271-5.
Sivolella S, Valente M, Gasparini E, Stellini E. Nasopalatine duct cyst as a complication of dental implant placement: A case report. Minerva Stomatol 2013;62:235-9.
McCrea SJ. Nasopalatine duct cyst, a delayed complication to successful dental implant placement: Diagnosis and surgical management. J Oral Implantol 2014;40:189-95.
D'Addona A, Nowzari H. Intramembranous autogenous osseous transplants in aesthetic treatment of alveolar atrophy. Periodontol 2000 2001;27:148-61.
Palacci P, Nowzari H. Soft tissue enhancement around dental implants. Periodontol 2000 2008;47:113-32.
Ioannidis JP, Trikalinos TA. Early extreme contradictory estimates may appear in published research: The proteus phenomenon in molecular genetics research and randomized trials. J Clin Epidemiol 2005;58:543-9.
Dal-Ré R, Janiaud P, Ioannidis JP. Real-world evidence: How pragmatic are randomized controlled trials labeled as pragmatic? BMC Med 2018;16:49.
Rodriguez AE, Monzavi M, Yokoyama CL, Nowzari H. Zirconia dental implants: A clinical and radiographic evaluation. J Esthet Restor Dent 2018;30:538–44.
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