Summary of studies with a conservative focus for the management of ONJ-related osteonecrosis [55].
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"intechopen-signs-new-contract-with-cepiec-china-for-distribution-of-open-access-books-20210319",title:"IntechOpen Signs New Contract with CEPIEC, China for Distribution of Open Access Books"},{slug:"150-million-downloads-and-counting-20210316",title:"150 Million Downloads and Counting"},{slug:"intechopen-secures-indefinite-content-preservation-with-clockss-20210309",title:"IntechOpen Secures Indefinite Content Preservation with CLOCKSS"},{slug:"intechopen-expands-to-all-global-amazon-channels-with-full-catalog-of-books-20210308",title:"IntechOpen Expands to All Global Amazon Channels with Full Catalog of Books"},{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"}]},book:{item:{type:"book",id:"1311",leadTitle:null,fullTitle:"Advances in Cancer Therapy",title:"Advances in Cancer Therapy",subtitle:null,reviewType:"peer-reviewed",abstract:"The book \"Advances in Cancer Therapy\" is a new addition to the Intech collection of books and aims at providing scientists and clinicians with a comprehensive overview of the state of current knowledge and latest research findings in the area of cancer therapy. For this purpose research articles, clinical investigations and review papers that are thought to improve the readers' understanding of cancer therapy developments and/or to keep them up to date with the most recent advances in this field have been included in this book. 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Prevalence, Risk Factors and Role of Microbiota and Inflammation in a Population of Spain",doi:"10.5772/intechopen.69315",slug:"osteonecrosis-of-the-jaws-prevalence-risk-factors-and-role-of-microbiota-and-inflammation-in-a-popul",body:'\nThe term osteonecrosis dates back to the 1950s, when a series of cancer patients who underwent radiotherapy developed bone lesions on the jaws following the treatment [1–3]. This treatment, which is currently resulting in many complications on an oral level, makes it very hard to cure infections that are sometimes inevitable for these patients, since ischemia takes place on the jaws.
\nSome years later, the first article appeared citing a periapical lesion following arsenic infiltration for canal treatment. Arsenic was used as a therapeutic agent and as poison in Ancient Greek and Roman times [4]. It was also used as an agent during dental history for pulp devitalization, when anesthetics did not exist. Due to its ability to destroy cells in surrounding tissues, the use of arsenic trioxide in vital pulpectomy has been dropped progressively [5]. Dumlu’s article (2007) described a case of jaw necrosis in a young patient following tooth extraction of a first failed molar after arsenic treatment of the canals [6]. Toxavit, another devitalizing agent, has also been related to bone necrosis. In any case, both agents are currently obsolete for these dental treatments [7, 8].
\nAnother one of the causes mentioned in the history of osteonecrosis is the untreated intracapsular fracture, after several months, the described clinical symptoms were pain in the temporal-jaw articulation in the affected side and the limitation in opening the jaw. On a radiographic level, the condylar head is usually eroded and irregular [9].
\nBack in 1982, the first cases of osteonecrosis of the jaw in toothless patients by chemotherapy treatment were published. Specifically, the article considered the origin was a lesion on the mucosa due to a trauma caused by removable prosthesis.
\nThe cases of aseptic osteonecrosis after jaw osteotomy following orthognathic surgeries have also been described in the literature; they have been related mostly to a complication following a surgical error [10].
\nIn 2002, a clinical case of osteonecrosis of the jaws due to chemotherapy in a patient with myelogenous leukemia was published [11]; and, a year later, the current term bisphosphonates-related osteonecrosis of the jaws was branded (BRONJ) [12].
\nDespite the osteonecrosis of the jaws was exclusively related to the mouth, some rare cases in the external ear, the hip, the tibia and the femur have been documented [13, 14].
\nThe concept of osteonecrosis of the jaws was introduced in 2003 when a series of 36 bone lesions in the mandible and the maxilla were described in patients undergoing treatment with pamidronate or zoledronate [12].
\nThen in 2007, the American Association of Oral and Maxillofacial Surgeons (AAOMS) described osteonecrosis of the jaws like persistent bone exposure in the mouth for over 8 weeks in patients with a history of use of bisphosphonates, without local evidence of malignancy or radiotherapeutic treatment of the affected region [15].
\nDespite that the term osteonecrosis has been used in numerous contexts and even in different locations (not only for the jaws); it is currently related exclusively to the chronic use of bisphosphonates. The condition is called bisphosphonate-related osteonecrosis of the jaw (BRONJ) [16], which was changed by the AAOMS in 2014 for the term medication-related osteonecrosis of the jaw (MRONJ), since this complication has also been described in relation to other antiresorptive drugs (denosumab) and antiagiogenic therapies [17].
\nThe prevalence of osteonecrosis of the jaws is variable according to the consulted authors, reaching approximately 7–12%, although in more recent articles it tends to be even higher (18.6%) [18].
\nIn regards to IV bisphosphonates, the bibliography of a series of cases, case studies and controls and cohorts, the estimations of the accumulated incidence of MRONJ ranges from 0.8 to 12% [19].
\nIn regards to oral bisphosphonates, clinical effectiveness has been proven, which is shown in over 190 million prescriptions of these drugs around the globe [20]. Despite that osteonecrosis cases have been described, these patients have a considerably lower risk of MRONJ than cancer patients who have been treated with monthly IV bisphosphonates.
\nAccording to the database of the alendronate manufacturer (Merk), the incidence of MRONJ was calculated as 0.7/100.000 people/years of exposure [21]. This derives from the number of (non-confirmed) reports of the cases that were considered as MRONJ, divided between the number of alendronate pills prescribed since the approval of the drug. Although this is the best information available to date, there could be a bias in the collection and validity of the data.
\nIn Australia, MRONJ incidence in patients receiving weekly alendronate treatment ranges between 0.01 and 0.04% [22]
\nFelsenberg registered a prevalence of MRONJ among patients who underwent bisphosphonates therapy for osteoporosis of 0.00038%, based on the reports of three cases in the German Central Register for Jaw Necrosis [23].
\nExtractions
Dental implants
Periapical surgery
Periodontal surgery
Cancer patients treated with IV bisphosphonates and who underwent dentoalveolar procedures had 5–21 times more risk of MRONJ than cancer patients who were treated with IV bisphosphonates and who did not undergo dentoalveolar procedures [19].
\nB1.
Lingual torus
Mylohyoid line
B2.
Palatine Torus
The lesions are located with a higher frequency on the mandible than on the superior maxilla (2:1) and more frequently in areas with thin mucosa that cover bone protrusions, such as the torus, bone exostosis and the mylohyoid edge [24–26].
\nPatients diagnosed with MRONJ are defined by the following characteristics [17]:\n
Prior treatment with antiresorptive and antiangiogenic drugs.
Presence of bone exposure or intra- or extraoral fistula for over 8 weeks, without remission.
Patients who have not been treated with radiotherapy nor have metastasizing diseases in the jaws.
With the intention of standardizing all the signs and symptoms present in the patients affected by osteonecrosis of the jaws, a protocol for MRONJ diagnosis was proposed in 2010 [36].
\nExposed necrotic bone in the oral cavity
Abscess
Displacement of jaw fragments
Intra-extra oral fistula
Jaw deformation
Lip hypaesthesia/paraesthesia
Gum or mucous fistula
Nasal level excretions
Unhealed post-extraction alveoli
Pus excretion
Spontaneous expulsion of bone sequestration
Dental mobility
Local inflammation
Bone and dental pain
Trismus
Cortical fracture
Sclerosis of the focal bone marrow
Presence of post-extraction alveoli
Trabecular engrossment
Diffuse sclerosis
Oro-antral fistula
Osteolysis extended to the sinus floor
Osteosclerosis of adjacent bones (zygoma and hard palate)
Pathological fracture
Prominence of the lower dental nerve canal
Sinusitis
The histopathologic study and microbiological culture are also tests developed on the suppuration area. Developing an antibiogram is very helpful since these patients will be treated with antibiotics during long periods of time and it is convenient to know the existing bacterial spectrum and the sensitivity of these microorganisms to different antibiotics.
\nThe stages initially described by Ruggiero et al. [24] have been modified and adapted to classify patients with greater precision [17, 19, 39] (Figure 1).
\nTNM Staging. (A) Stage 1; (B) Stage 2; (C) and (D) Stage 3.
Odontalgia without odontogenic cause.
Pain at the jaw level that may irradiate to the temporomandibular joint.
Sinus pain, which may be related to inflammation or engrossment of the maxillary sinus wall.
Alteration of the neurosensory function
Dental loss without periodontal cause
Periapical or periodontal fistula that is not related to a pulpal necrosis by cavities.
Bone resorption that is not attributable to chronic periodontal disease.
Changes to the trabeculate and bone density and resistance to healing of the post-extraction alveoli.
Widening/darkening of the periodontal ligament.
Narrowing of the lower dental nerve canal.
These unspecific findings that are characteristic of State 0 can take place in patients with a prior history of more advanced phases in whom the disease has been cured and have no clinical evidence of exposed bone.
\nExposed necrotic bone beyond the alveolar region, as the lower border of the mandibular branch, maxillary sinus or zygoma.
Pathological fracture.
Oro-antral and oro-nasal communication.
Extra-oral fistula.
To focus on the treatment to be developed regarding this complication, it is essential to know the pathophysiology of MRONJ, only by this way we can draft an appropriate treatment plan.
\nTo date, the source has not been adequately documented, describing a multi factor source. Suppression of bone remodeling can contribute to the development of osteonecrosis by an inadequate activity of osteoclasts that do not allow the post-extraction alveoli to heal. The presence of microflora in the mouth have also been related as an osteonecrosis-promoting factor, since numerous biopsy studies and bone sequestrations revealed the presence of
Additionally, recent articles relate the presence of Actinomyces in MRONJ, although these are small studies on a series of cases having a very small impact in establishing a specific treatment strategy [28, 44–46].
\nAntinomyces are Gram-positive anaerobic facultative bacteria that do not form spores and are commonly filamentous. They are frequent commensals of the mucosa in the oropharynx, intestinal tract and the female genital tract, once the mucosa barrier is broken due to trauma, surgical interventions or foreign objects, they can invade deep tissue structures and compromise treatment response. Progressive chronic disease is called actinomycosis, and the treatment of this pathology is based on a prolonged antimicrobial therapy for 2–6 months in combination with surgery [47, 48].
\nAmoxicillin with or without clavulanic acid (500 mg/l g)
Clindamycin (300 mg)
Azithromycin (500 mg)
Metronidazole with betalactamic antibiotics
Numerous studies have used this therapy as an adjuvant in antibiotic treatments with good results, although further standardized studies are needed to accurately determine their effectiveness [50].
Most conservative treatments on their own do not show accurate results on their effectiveness, especially in more advance stages. Authors use them in combination with antibiotics and observe that these can help heal the patient, especially in terms of tissue regeneration; but it is always reinforced with an appropriate antibiotic treatment (Table 1) [55].
\nType of treatment | \nAuthor/Year | \nNo. patients healed/No. patients treated (%) | \n
---|---|---|
Antibiotic treatment | \nMelea et al. (2014) | \n23/38 (60%) | \n
Van den Wyngaert et al. (2009) | \n16/33 (53%) | \n|
Scoletta et al. (2010) | \n18/30 (62%) | \n|
Nicolatou-Galitis et al. (2011) | \n7/47 (14.9%) | \n|
T Antibiotic treatment + hyperbaric oxygen | \nFreiberger et al. (2012) | \n13/25 (52%) | \n
Antibiotic treatment + ozone therapy | \nRipamonti et al. (2011) | \n10/10 (100%) | \n
Pentoxifylline + α-tocopherol | \nMagremanne et al. (2014) | \n1/1 (100%) | \n
Summary of studies with a conservative focus for the management of ONJ-related osteonecrosis [55].
For patients in advanced stages and resistant-clinical-cases:
\nNumerous studies show high improvement rates in patients who underwent surgical treatment both in conservative and resective procedures (Table 2) [55].
\nType of treatment | \nAuthor/Year | \nNo. patients healed/No. patients treated (%) | \n
---|---|---|
Conservative surgery | \nRugani et al. 2014 | \n15/17 (88.2%) | \n
Vescovi et al. (2012) | \n11/17 (65%) | \n|
Thumbigere-Math et al. (2009) | \n3/19 (15%) | \n|
Williamson et al. (2010) | \n40/40 (100%) | \n|
Vescovi et al. (2014) | \n25/27 (92.6%) | \n|
Graziani et al. (2012) | \n227 (54%) | \n|
Wutzl et al. (2008) | \n24/41 (519%) | \n|
Conservative surgery + ozone therapy | \nAgrillo et al. | \n57/94 (60%) | \n
Conservative surgery + L-PRF | \nKim et al. | \n26/34 (77%) | \n
Resect1ve surgery | \nGraziani et al. (2012) | \n87/120 (72.5%) | \n
Carlson and Basile (2009) | \n87/95 (92%) | \n|
Bedogni et al. (2011) | \n27/30 (90%) | \n|
Voss et al. (2012) | \n20/21 (95%) | \n|
Schubert et al. (2012) | \n47/54 (87%) | \n
Summary of studies with a surgical focus for the treatment of MRONJ.
Note: L-PRF (leukocyte- and platelet-rich fibrin).
The use of stem cells [58, 59], platelet-rich plasma [60], the administration of parathyroid hormone [61] or the use of leukocyte- and platelet-rich fibrin [62] are also promising proposals, but they require further clinical studies that attest to their effectiveness.
\nSurgical debridement of the necrotic bone
Antibiotic therapy (oral or IV)
Analgesics
Daily rinses with antimicrobial agents (chlorhexidine at 0.12%)
Regardless of the state of the patient, mobile bone sequestration segments must be retrieved. Extraction of affected teeth with symptoms within the exposed necrotic bone must be considered, since it is improbable that the extraction exacerbates the established necrotic process.
\nDespite all the treatments proposed above, the latest articles agree that none of these are completely effective for all cases, therefore, the main goal in these patients is prevention of this complication.
\nBack in 2009, AAOMS [16] determined that prevention was the main goal in the management of these patients, recommending that patients are evaluated and treated before initiating bisphosphonate therapy.
\nThere are several studies that document that preventative dental treatment decreases the risk of MRONJ among patients with malignant tumors treated with IV bisphosphonates [63, 64]. These findings suggest that, although MRONJ is not eliminated, evaluations and dental treatment prior to beginning bisphosphonate therapy in cancer patients reduces the risk of MRONJ.
\nFurthermore, they advise revising the doses prescribed to the patients, since it has been proven that [65] the accumulative doses can increase the risk of suffering complications.
\nThe risk of developing MRONJ due to oral bisphosphonate treatment is minimal, but it seems to increase when the duration of the treatment is more than 3 years. This period of time can be reduced in the presence of certain concomitant diseases, such as the chronic use of corticosteroids. Systemic conditions permitting the clinician should consider interrupting oral bisphosphonate treatments for a 3-month period before and another 3 months after elective invasive dental surgery with the purpose of reducing the risk of MRONJ. The justification of this focus is based on extrapolated data that show fluctuations depending on osteoclasts, which is related to the treatment with bisphosphonates, and recent studies show that there is a better result in the treatment of MRONJ after eliminating the drug [66]. In the long term, prospective studies will be necessary to establish the efficacy of suppression period of these drugs to reduce the risk of MRONJ in patients undergoing oral bisphosphonate treatments.
\nThe goal is to reduce the risk of developing MRONJ to the minimum despite that a small percentage of patients who receive IV bisphosphonate therapy can develop osteonecrosis spontaneously [19]. Thus, if the medical conditions of the patient allow, the start of the treatment must be delayed until their dental health is optimal [63, 64]. This decision must be made by the doctor, together with the dentist and other specialists involved in the patient’s care.
\nUntreatable teeth and those with bad prognosis must be extracted. Additionally, other necessary dentoalveolar surgeries should also be performed at this time. The start of the treatment with bisphosphonates, if possible, should be delayed until complete healing of the mucosa (14–21 days) or until there is an appropriate bone healing.
\nDental prophylaxis, cavity control and restorative-conservative odontology are essential to maintain dental health. This level of attention should be maintained indefinitely. The patients with complete or partial prosthesis should be examined to avoid the trauma areas of the mucosa, especially in the border of the tongue. It is essential that patients are trained in regards to the importance of oral hygiene and regular dental evaluations, and instructed specifically to report any pain, swelling or exposed bone area.
\nProcedures that imply direct bone lesion should be avoided, therefore, unrestorable teeth should be treated by eliminating the crown and the endodontic treatment of root fragments [21]. The placement of dental implants must be avoided in cancer patients exposed to higher potency bisphosphonates (zoledronic acid and pamidronate) with a frequent dose program (4–12 times/year).
\nIn general terms, these patients seem to have less severe manifestations of necrosis and respond promptly to the described treatments [67, 68]. Elective alveolodental surgery does not seem to be contraindicated in this group, although it is advisable that the patients are appropriately informed on the small risk of complications in bone healing. The use of levels in the bone exchange markers and a drug break in the treatment have been documented as additional tools that guide in making treatment decisions in patients exposed to oral bisphosphonates [68]. Currently, the effectiveness of the systemic markers of bone exchange to assess the risk of developing jaw necrosis in risk patients is being questioned, which requires more research before considering it as a valid risk evaluation tool. In the long term, prospective studies will be necessary to establish the efficacy of suppression period of these drugs (drug holidays) to reduce the risk of MRONJ in these patients.
\nThe risk of MRONJ seems to be more associated to the duration of the treatment (≥3 years) than the dosage, since there has not been any information indicating that the monthly dosage of bisphosphonates is related, with a high or reduced risk of MRONJ when it is compared with the weekly dose program.
\nThere a no solid recommendations based on clinical research for patients who take oral bisphosphonates. The Task Force strategies described above have remained essentially unchanged and are based on the clinical experience of the physicians (expert opinions) who participate in the care of these patients [24, 64, 68–70].
\nIncludes all the common procedures for oral and maxillofacial surgeons, periodontists and specialists.
\nIf dental implants are placed, an informed consent must be presented in regards to possible implant failure and the possible osteonecrosis of the jaws, if the patient continues the oral bisphosphonate treatment. It is also advisable to contact the doctor who initially prescribed the oral bisphosphonate to suggest monitoring of these patients and consider a possible alternative dose to the bisphosphonate, temporary suppression of the drug or an alternative to the medication.
\nIf systemic conditions allow, the physician must be contacted to consider the interruption of the oral treatment for at least 3 months prior to the oral surgery. Reinstatement of bisphosphonate therapy should not take place until complete bone healing. These strategies are based on the opinion of experts with significant clinical experience and the hypothesis that concomitant treatment with corticosteroids can increase the risk of developing MRONJ.
\nIf systemic conditions allow, the physician must be contacted to consider the interruption of the oral treatment for at least 3 months prior to the oral surgery and, similarly, bisphosphonate therapy should not be reinstated until complete bone healing.
\nThis bone resorption biomarker has been used for years as a predictive factor for the development of bisphosphonate-related osteonecrosis when deciding on the dental treatments for this type of patients [71]. In a study by Marx et al. (2007), they observed CTXs in fasting samples to correlate the values and the period of use of oral bisphosphonates and to demonstrate if the increase in value could indicate a recovery in bone remodeling when suspending oral bisphosphonate treatment. Risk stratification was determined according to the obtained values, CTX under 100 pg/ml represented high risk, CTX between 100 pg/ml and 150 pg/ml represented moderate risk, while CTX above 150 pg/ml represented minimal risk. CTX values increased between 25.9 and 26.4 pg/ml for each drug holiday month from the bisphosphonates, which indicated a recovery of the bone remodeling and a directive in terms of when the oral surgical procedures could be developed at a lower risk. Additionally, it was observed that in terms of the drug suppression periods associated to CTX values, the latter rose above the threshold of 150 pg/ml, which coincides with spontaneous bone healing or a better response to complete healing after debridement. [68].
\nAfter years of research, a meta-analysis of nine controlled studies did not reveal significant differences in the mean values of CTXs among patients with MRONJ and controls (mean difference, −31.417; 95% confidence interval [CI], −91.560 to 28.726; P = 0.306). Additionally, a second meta-analysis of four studies did not show significant differences in the risk of osteonecrosis with CTX values below 150 pg/ml for patients with MRONJ in comparison with the controls (risk ratio, 1.892; 95% CI, 0.636–5.626; P = 0.251) [71].
\nThe term
Guideline | \nBisphosphonate exposure history by route of administration | \n|
---|---|---|
Oral | \nIntravenous | \n|
ASBMR56 | \nNo specific guidelines given | \nNo guidelines given | \n
AAOMS57 | \nLess than 3 year duration: | \nNo guidelines given | \n
\n | No change to dosing | \n\n |
\n | Less than 3 year duration and corticosteroids: | \n\n |
\n | Cease: 3 months prior | \n\n |
\n | Recommence: Osseous healing has occurred† | \n\n |
\n | More than 3 year duration: | \n\n |
\n | Cease: 3 months prior | \n\n |
\n | Recommence: Osseous healing has occurred† | \n\n |
CCPG60 | \nNo specific guidelines given | \nCease: 3–6 months prior | \n
\n | \n | Recommence: Full healing† | \n
Mayo Clinic62 | \nNo guidelines given | \nCease: 1 month prior | \n
\n | \n | Recommence: Full healing | \n
MFA64 | \nNo guidelines given | \nLow/intermediate risk of SRE: | \n
\n | \n | Cease: 2–3 months prior | \n
\n | \n | Recommence: 2–3 months after or full healing | \n
Cancer patients benefit mainly from the therapeutic effects of bisphosphonates, such as the control of bone pain and the incidence of pathological fractures. An interruption of IV bisphosphonate therapy does not offer short-term benefits. However, if systemic conditions allow, long-term suspension can be beneficial in the stabilization of the areas affected by MRONJ, which reduces the risk of necrosis in other locations and minimizes clinical symptoms [63, 64]. The oncologist’s role is very important to assess the risks and benefits of suppressing the treatment.
\nRegarding the interruption of oral bisphosphonate treatment in patients with MRONJ, a gradual improvement of the disease has been proven [68]. The interruption of oral bisphosphonates for 6–12 months may favor healing, after the removal of a bone sequestration or after debridement. The decision to suppress the drug must be assessed by the physician and the patient, as long as the systemic conditions allow.
\nBisphosphonates are non-metabolizable pyrophosphate analogues that are deposited on the bones and prevent or improve bone complications of the patients with bone alterations. Different bisphosphonates differ depending on the alterations of the R-2 lateral chain structure. These R-2 lateral chains determine the efficiency and the cellular effects of the inhibition of bone resorption [73]. The bisphosphonates are internalized by osteoclasts, causing the interruption of bone resorption. They also have antigiogenic properties, since they reduce the circulating levels of vascular endothelial growth factor (VEGF) [74–78] and antineoplastic effects [79]. It has very little intestinal absorption and is excreted without being metabolized by the kidneys.
\nUntil 2001, pamidronate (Aredia®) was the only drug approved in the USA for the treatment of bone metastasis. In 2002, the US Food and Drug Administration (FDA) [80] approved zoledronic acid (Zometa®) as a treatment for these patients. Currently, the annual transfusion of zoledronate (Reclast®) and the parenteral formulation of ibandronate (Bonviva®) administered every 3 months has been approved by the FDA for the treatment of osteoporosis [81].
\nIn 2003, using the articles by Marx [12] and Ruggiero et al. [25], they observed and reported on the cases of unhealed bone exposure in the maxillofacial region in patients treated with IV bisphosphonates and, after multiple further publications, in September 2004, Novartis the manufacturer of pamidronate (Aredia®) and zoledronic acid (Zometa), added the complications deriving from this treatment to the labeling of these drugs, with the purpose of warning the health care professionals of the possibility of developing osteonecrosis of the jaws [82].
\nAccording to their chemical structure, these are divided into two groups.
\nThere is a great variety of bisphosphonates approved for clinical use in the USA (Table 4).
\nGeneric name | \nCommercial name | \nLaboratory | \nRP | \nFDA-a | \n
---|---|---|---|---|
Pamidronate | \nAredia, IV | \nNovartis | \n100 | \n1991 | \n
Tiludronate | \nSkelid, O | \nSanofi | \n10 | \n1997 | \n
Alendronate | \nFosamax, O | \nMerck | \n1000 | \n1997 | \n
Etidronate | \nDidronel, O | \nProctor & Gamble | \n1 | \n1997 | \n
Risedronate | \nActonel, O | \nProctor & Gamble | \n5000 | \n1998 | \n
Zoledrónic acid | \nZometa, IV | \nNovartis | \n100,000 | \n2001 | \n
Ibandronate | \nBonviva, O | \nRoche | \n10,000 | \n2005 | \n
Drugs approved in EEUU.
Note: O: oral; IV: intravenous.
It is estimated that over 2.8 million cancer patients from around the world have received treatment with IV bisphosphonates since their introduction [84].\n
It is a heterocyclic imidazole and, to date, the most powerful bisphosphonate to be administered to humans. In a test on in-vitro bone resorption using mouse cranium, zoledronate was at least 100 times more powerful than pamidronate. Additionally, the in-vivo animal model of calcitriol-induced hypercalcemia in thyroparathyroidectomized rats was 850 times more active than pamidronate and over 4 times more powerful than clodronate. Of all the bisphosphonates under clinical evaluation, this is the one having a higher therapeutic relationship between the desired inhibition of bone resorption and the undesired inhibition of bone mineralization, furthermore, several toxicology studies proved that the compound is safe [85].
\nDue to the proven clinical effectiveness, it is considered a first line therapy in the treatment of osteoporosis and they are the most prescribed antiresorptive agents.\n
It has been proven to prevent approximately 50% of cases in the prevention of the bone loss in the spine or hips in menopausal women and the reduction of bone fractures [86, 87].\n
In a prospective study with a large sample, risedronate produced a reduction of 30% in hip fractures [88, 89].\n
Bisphosphonates have an average life between 30 min and 2 h and are deposited in the locations with higher bone metabolism, and can remain at the bone level for approximately 10 years. The highest concentration is located in urine and saliva, and the most frequent adverse effects are renal insufficiency and osteonecrosis [90–92]. The accumulative doses described by Maerevoet, is of 72 mg for 18 months [90, 93].
\nIn the case of IV bisphosphonates, such as zolendronic acid, 40% is eliminated unaltered through urine after 24 h [94] and the remaining 60% are united at bone level due to the great affinity of hydroxyapatite. This phenomenon takes place in areas of bone remodeling, in which the periodical exchange produces unaltered kidney excretion after a long elimination phase [95]. The mean life of this second elimination phase may last months or years, depending on the duration of the bisphosphonate treatment [96].
\nExcretion of oral bisphosphonates has also been studied, for example, in a rat study, in which they administered risedronate orally, and determined that 80% of the drug was excreted through the kidneys 12 h after the administration of the drug. Additionally, the study concluded that taking oral bisphosphonates with mineral water that contains high calcium and magnesium levels reduced the effect of the drug; therefore it is advisable to take it as soon as the patient wakes up and in a vertical position [97]. These authors previously described the effect of water in combination with taking alendronate [98].
\nThe concentration of bisphosphonates in a specific bone location depends on the speed of bone remodeling and blood circulation [99]. It is important to know the concentration of accumulated bisphosphonate in the bone to understand the long-term drug effect and its toxicity. Today, numerous authors have been able to quantify these drugs in plasma and urine through mass spectrometry (MS), which requires a previous derivation process that allows to transform the bisphosphonates into more hydrophobic substances so they can be studied [100, 101].
\nThe development of analysis methods for the detection of bisphosphonates in biological matrices, it is hard due to the chemical properties of these compounds. The detection of bisphosphonates in human biological matrices comes with certain difficulties and therefore a broad range of analytic techniques have been described, such as gas chromatography [102], ion chromatography [103], capillary electrophoresis, ionization mass spectrometry by electrospray [104] and chromatography of fluids [105].
\nA method for the extraction and detection of zoledronic acid in urine and blood plasma or even accumulated in the bone (in a mouse model) through the combination of chromatography and mass spectrometry (MS) [100, 106].
\nIn these studies, a higher accumulation of bisphosphonates in bone extracts of the mandible was detected, compared to other types of bones [106]. On the other hand, human urine and blood plasma detected a maximum concentration peak of the drug of 77 μM (5 h after the administration) and 1.5 μM (after 1 h), respectively [100]. This methodology achieves high sensitivity and specificity in the detection, however, it requires a pretty complex and arduous treatment of the sample requiring phases with chemical reactions to derive the complex. The complexity of the treatment of the sample can be a limiting factor when the number of samples to be analyzed is high, as in the case of the follow-up of the pharmacokinetics and the bioavailability of zoledronic acid since its administration. For this reason, it would be desirable to have a more efficient alternative method to detect this drug.
\nNuclear magnetic resonance (NMR) spectroscopy is a useful technique in chemometrics that can be used for the characterization of simple or complex mixes of different sources and provide quantitative results. There is a great variety of “omics” applications for NMR, such as
It is a quantitative technique that allows determination of the absolute concentration of diluted substances in general, including biofluids. It is based on the fact that the intensity of a signal in the NMR spectrum is proportionate to the concentration of the molecule (or metabolite) generating the said signal. As an approximate value, to assess the sensitivity of this technique, in a current spectrometer with a 11.7 T magnet, the minimum concentration required to detect a molecule in a monodimensional spectrum (1D) of 1H (proton spectrum, as it is commonly known in our jargon) must amount to a minimum of 10 μm, for a measurement period of 15 min.
\nFor the case of urine samples, under these same measurement conditions, 50–60 metabolites can be identified and quantified in their proton spectrum (Figure 2).
\nTypical spectrum of 1H NMR of a human urine sample. The numbers indicate the following metabolites: 1: creatinine, 2: citric acid, 3: glycine, 4: formic acid, 5: methanol, 6: guanidinoacetic acid, 7: acetic acid, 8:
When a series of NMR spectra need to be compared, such as urine, it is important to consider some details regarding post-processing of the spectra and the process to obtain their quantitative values, in such a way that no errors are introduced in this phase and the quantitative results that are obtained are the most precise and repeatable as possible. Although with slight variations regarding some details, the general method for the treatment of spectral information for the metabolomic studies by NMR is the one described below.
\nA series of protocols have been established for the preparation of biofluid samples and their subsequent preservation until the NMR measuring [112, 113]. Similarly, there are experimental parameters to be used for the measurement of the NMR spectrum for each type of biofluid [112, 113]. These protocols standardize the measurements, thus allowing the comparison of the spectra obtained and the NMR spectrum (e.g. the Human Metabolome Database: www.hmdb.ca) and/or with bibliographic results. These sample preparation protocols tend to be simple and do not require special laboratory equipment.
\nThe raw data provided by the spectrometer when measuring the 1H NMR spectrum is called free induction decay (FID). The data must be post-processed by applying a series of operations to generate a final spectrum with a scale of frequencies (expressed by standardized ppm units) and with the best quality possible [114]. Once the post-processing has been completed for each of the spectra to be studied, the following phase consists of comparing analogue regions of the spectrum with the target to find, if possible, a certain region that could serve as a biomarker, in other words, a region in which the signal’s intensity pattern is significantly different in the samples of the control group and the experiment group, while being similar within their own group.
\nInstead of manually selecting one or several regions for comparison, the usual and practical procedure is to perform a systematic analysis, dividing the entire spectrum automatically, from right to left, through a series of small segmental regions (e.g. with an established width) in which the area of the signal is integrated individually. Each of these regions is called buckets or regions of interest (ROIs). This way, a complete spectrum is represented as a data vector formed by the integrals of the selected ROIs, with as many integral values as segments of the spectrum have been created.
\nLastly, a table is created with the data, placing the vectors of each of the analyzed samples in different lines (Figure 3). There are software tools that automate these operations to generate the data table, as well as the phase before the post-processing.
\nScheme for the construction of a NMR ROI data matrix from 53 NMR spectra. Above: 53 1H spectra in which we have selected certain ROIs for the integration of the signal. The vertical piling scale identifies each of the samples (# sample). The same color has been used to identify samples that should be, a priori, of the same type. Below: NMR ROIs data matrix obtained through the integration of each of the ROIs.
Of the ROI matrix integral values, the negative values are initially purged since they only contain noise (a ROI must have at least an integral value or a signal area that equals zero).
\nThe ROIs data standardization process seeks to take all the analyzed samples to a “virtual” constant that eliminates all the differences in global concentration in the ROI integral samples, which could simply respond to the urine having a higher or lower concentration of H2O. When the dilution effect is eliminated, the differences between values of the same ROI in a pair of samples directly reflect variations in the relative concentration of the studied metabolite.
\nA first standardization method consists of standardizing the total addition of the ROIs. This method considers that the total addition of all the ROIs of the same spectrum has a constant value, and that this is the same for all the samples. This type of standardization by matrix lines consists of dividing each ROI value by the total addition of ROIs of its same line. As a result, the standardized ROIs of a sample add up to the unit.
\nThis method consists of using the data of the ROIs of a certain sample of the study (a line of the matrix) and dividing the ROIs between those of another sample that is used as reference. This allows us to deduce the most probable multiplication factor so that the ROIs of the first sample are as close as possible to the reference sample. The most probable multiplication factor is calculated for each sample (for each line of the matrix). As a result of applying each factor on the ROIs of the relevant samples, their ROIs will be standardized as if the sample would have been prepared in the same concentration as the reference sample [115].
\nThe Matrix of standardized ROIs is analyzed by multivariate statistic methods to identify the ROIs that contain similar or different patterns of the integral in samples of the same or different group and their potential biomarkers. To do this, algorithms, such as the Principal Components Analysis (PCA), Discriminant Analysis (DA) and Orthogonal Projections to Latent Structures-Discriminant Analysis (OPLS-DA) are used. These algorithms have been implemented in several general statistical software packages, for example, R, SPSS or XLSLAT, among others.
\nIn favorable cases, one or more ROIs with potential biomarkers related to the property under investigation are identified, for example, the effect of certain medical treatments, a type of diet, a disease, etc. Additional objectives can then be included in the study, such as the identification of what specific biomarkers (metabolites) were altered compared to the control group, to try to discover through which metabolic pathway they underwent this change. Some of the biomarkers that are identified as different from the control group may not correspond to any of those that are typically found in the relevant type of biofluid, but they may proceed from the metabolism of a drug or a special diet that has been prescribed. In this case, once its NMR signal has been identified, we could consider performing a longitudinal follow-up on its appearance in the biofluid since its administration.
\nCurrently, two types of drugs, aside from bisphosphonates, have been proven to cause necrosis of the jaws.
\nIt is a RANKL monoclonal antibody that is currently still undergoing clinical trials for the treatment of osteoporosis, primary and metastatic bone cancer, giant cell tumor and rheumatoid arthritis [116, 117]. RANKL is necessary for the activation and function of mature osteoclasts [118, 119], which together with osteoprotegerin (OPG), maintains the balance of bone resorption in a healthy state. When an imbalance occurs in the RANKL/OPG ratio, resorption is favored in bone diseases [120, 121].
\nDenosumab has a high specificity due to human IgG2 that binds specifically to human RAN, and not other members of the TNF superfamily [116, 122, 123]. In clinical trials, this drug causes rapid and prolonged decreases in bone exchange markers without any change in bone formation, which gives it antireabsorptives characteristics [124]. It has also shown better clinical results compared to bisphosphonates in the treatment of osteoporosis and cancer with a higher increase in bone density and suppression of bone remodeling markers, with a proven efficacy even in patients who had been previously resistant to bisphosphonates [117, 125, 126].
\nThese drugs also produce osteonecrosis of the jaws with a prevalence of 0.7–19% [127, 128], which is very similar to the osteonecrosis from bisphosphonate treatments [117]. Since the first case of maxillary osteonecrosis due to this drug published in 2010 [129], several studies have been published but only one of them describes histopathologic characteristics [130]. The fragments of necrotic bone showed empty osteocytic lacuna and absence of osteocytes, osteoblasts and osteoclasts. The authors suggest that these characteristics are very similar to bisphosphonate-related osteonecrosis [131]
\nThese drugs hinder the development of new blood vessels and block the cascade of angiogenesis [132].
\nAll the patients of this study visited the Master of Oral Medicine, Surgery and Implantology of the Faculty of Dentistry of the University of Santiago de Compostela. The patients were derived from the Unit of Oncology of the Complejo Hospitalario Universitario de Santiago de Compostela (CHUS) for a dental examination prior to treatment with intravenous bisphosphonates. The study was approved by the Clinical Research Ethics Committee of Galicia, in addition to the gaining informed consent from the patients.
\nPatients treated with zoledronic acid for a period of 7 years (2006–2013) and patients with a history of treatment of head and neck radiotherapy were excluded.
\nCharacteristics | \nTotal patients with ONJ (%) | \nTotal patients without ONJ (%) | \nP | \n
---|---|---|---|
\n | \n | 0.063 | \n|
Men | \n14 (7.2) | \n125 (64.4) | \n\n |
Women | \n11 (5.7) | \n44 (22.7) | \n\n |
\n | \n | 0.214 | \n|
Cancer | \n12 (6.2) | \n95 (49) | \n\n |
Prostate | \n9 (4.6) | \n34 (17.5) | \n\n |
Breast | \n4 (2) | \n11 (5.7) | \n\n |
Myeloma | \n0 (0) | \n18 (9.3) | \n\n |
Lung | \n0 (0) | \n2 (1) | \n\n |
Bladder | \n0 (0) | \n5 (2.6) | \n\n |
Colon | \n0 (0) | \n3 (1.5) | \n\n |
Kidney | \n18 (9.3) | \n176 (90.7) | \n\n |
Diabetes | \n168 (86.6) | \n26 (13.4) | \n0.048 | \n
Polymedicated. | \n94 (48.5) | \n100 (51.5) | \n0.139 | \n
HTA | \n42 (21.6) | \n152 (78.4) | \n0.704 | \n
Cortisone | \n65 (33.5) | \n129 (66.5) | \n0.234 | \n
QTP | \n11 (5.7) | \n54 (27.8) | \n0.462 | \n
\n | \n | \n | |
Extraction Before | \n8 (4.1) | \n86 (44.3) | \n0.078 | \n
Extraction during | \n5 (2.6) | \n1 (0.5) | \n<0.001 | \n
Extraction after | \n4 (2) | \n7 (3.6) | \n0.017 | \n
Prosthesis | \n5 (2.6) | \n33 (17) | \n0.936 | \n
periodontal state | \n19 (9.8) | \n70 (36) | \n0.001 | \n
\n | \n | 0.998 | \n|
Tobacco | \n2 (1) | \n13 (6.7) | \n\n |
Alcohol | \n3 (1.5) | \n19 (9.8) | \n\n |
\n | \n | \n | |
Unifocal mandible | \n13 (6.7) | \n– | \n<0.001 | \n
Unifocal maxilla | \n5 (2.6) | \n– | \n\n |
Multifocal mandible | \n3 (1.5) | \n– | \n\n |
Maxilla and mandible | \n4 (2) | \n– | \n\n |
Risk factors in the occurrence of ONJ.
We selected 28 patients (16 men and 12 women) with a mean age of 71.96 years, all of whom were treated in the Oncology Department of the Complejo Hospitalario Universitario de Santiago de Compostela (CHUS). They were referred to the Unit of Oral Surgery and Implantology of the Faculty of Medicine and Dentistry of Santiago de Compostela for a prior dental examination and for the follow-up of possible complications after treatment.
\nAll patients treated with both oral and intravenous bisphosphonates and those undergoing head and neck radiotherapy within an 8-year period were included (2006–2014). The diagnostic criteria followed were those determined by the AAOMS [15] for patients treated with bisphosphonates, while in the case of those undergoing radiotherapy, we included those who had bone exposure for more than 8 weeks.
\nSamples of exudates from bone exposure were sent to the Department of Microbiology to be processed under Gram staining and seeded in liquid medium (thioglycolate broth) and in solids (agar-blood and agar-chocolate for the growth of aerobic bacteria, Sabouraud agar for yeast growth and Schaedler agar for anaerobic growth). The seeded plates were incubated for 48 h at 37°C in a CO2 atmosphere and 72 h in anaerobic chambers. Identification of microorganisms was done using the Vitek 2 system (Bio-Merieux, Marcy l’Etoile, France) and Microscam (Siemens, Erlangen, Germany) in the case of aerobes; and API-ANA (Biomeriex) in the case of anaerobes. Antimicrobial susceptibility testing was performed by the e-test method (AB biodisk) and the Clinical Laboratory Standards Institute (CLSI) interpretation criteria were followed.
\nBiopsies of bone sequestration were sent to the Pathological Anatomy Service where they were fixed in 10% buffered formaldehyde and embedded in paraffin following standard processing. For evaluation, they were stained with hematoxylin/eosin, PAS and methenamine silver to visualize the colonies of Actinomyces. Their presence was evaluated semi-quantitatively and divided into scarce, moderately abundant or very abundant. In addition, the presence of acute inflammation (when polymorphonuclear neutrophil cells were observed), which was also quantified in three degrees: mild, moderate and intense, and the presence of chronic inflammation (indicated by the presence of lymphocytes and plasma cells).
\nThe collected data were analyzed with the SPSS statistical system, version 20.0 for Windows. The discontinuous quantitative or discreet variables were analyzed through descriptive statistics, expressing the results in mean, deviation and standard. The frequency tables and percentages were used for qualitative variables. For the study of the association of variables we employed the chi-squared test, the T-Student test or the ANOVA factor test, depending on the application conditions. Values in which P ≤ 0.05 were considered statistically significant.
\nOf the 28 patients, 16 were men (57.1%) and 12 women (48.8%) with a mean age of 71.96 years (SD 8.94). According to the risk factors analyzed, 8 patients (28.5%) were diabetic, 15 (53.6%) were undergoing chemotherapy, 4 were smokers (14.3%), 14 was hypertensive (50%) and 9 (32.1%) were taking corticosteroids. The reason for treatment with bisphosphonates was oral cancer (14.3%), breast cancer (25%), prostate cancer (39.2%), multiple myeloma (10.7%) and osteoporosis (10.7%).
\nThe most affected region of the mouth was the mandible (67.8%) followed by the upper jaw (21.4%) or both (10.7%).
\nThe degree of affectation was variable depending on the type of treatment. Patients on intravenous bisphosphonates had all stages of ONJ, whereas patients undergoing the oral treatment had only stage II ONJ and patients treated with radiotherapy showed both stage II (5%) and stage III (75%).
\nA total of 24 of 28 patients underwent a histological study with a biopsy of a bone sequestration lesion. Of these, in 21 patients (87.5%) we proved the presence of Actinomyces within the 3 degrees of osteonecrosis of the jaws. The amount of Actinomyces present was quantified semi-quantitatively by the pathologist. The pathogen count was very abundant in degrees I and II, while in degree III the patients had lower amounts of Actinomyces (Figure 4).
\nHistological image of bone sequestration. Histopathologic examination revealed different combinations of Actinomyces and the inflammatory response. Some cases showed abundant colonies of Actinomyces, but lacked any inflammatory infiltration (A); while in other examples this microorganism was identified along with a dense PMN infiltrate (B). PMNs were also seen in some cases, in the absence of Actinomyces (C). Last of all, in some patients, the only change consisted of fibrosis and the scarce inflammatory response was composed mainly of lymphocytes (D).
The degree of acute and/or chronic inflammation was also evaluated. In 54.2% of the patients, the presence of Actinomyces was not accompanied by any sign of inflammation; while in the rest of the patients, it was observed that as age increased, the intensity of the inflammation also increased; therefore a lower mean age accounted for the absence of inflammation (65.31; SD: 7.91) contrasting with abundant inflammation (81.00; SD: 2.83). Such differences were statistically significant (F = 5.270, P = 0.005). There was acute inflammation in 37.5% of the patients being quantified as mild inflammation (two patients), moderate (five patients) and severe (two patients); the latter two were present in patients with grade II osteonecrosis, exclusively. There were only two chronic inflammation cases, one patient with grade II and another with grade III ONJ.
\nThe relationship between the amount of Actinomyces present in the histological sections and the degree of inflammation observed in bone sequestration was evaluated. Despite not having statistically significant data, it was observed that the high amount of Actinomyces could trigger either null or an abundant inflammatory response (Table 6).
\n\n | Inflammation | \n||||
---|---|---|---|---|---|
Actinomyces | \nNull | \nMild | \nModerate | \nAbundant | \nChronic | \n
Null | \n0 | \n0 | \n1 | \n0 | \n0 | \n
Scarce | \n1 | \n0 | \n1 | \n0 | \n1 | \n
Moderate | \n8 | \n1 | \n1 | \n0 | \n1 | \n
Abundant | \n4 | \n1 | \n2 | \n2 | \n0 | \n
Relationship of the amount of Actinomyces and the inflammatory response.
Regarding the isolation of bacteria obtained through suppuration of the necrosed area, all the bacteria described by the microbiologist were recorded, which were later classified according to their aerobic or anaerobic metabolism. Aerobic bacteria were mostly found (85%) in patients with grade I and II of ONJ, being statistically significant (P = 0.002). However, anaerobic bacteria were present in 56% of the patients in the three stages of ONJ. Although all the cases of grade III presented anaerobic bacteria, this data were not statistically significant.
\nThere was practically no significance in the families of bacterial species specific to the different degrees of osteonecrosis, except
\n | Grade I | \nGrade II | \nGrade III | \nP value | \n
---|---|---|---|---|
0 | \n1 | \n1 | \n0.372 | \n|
2 | \nl | \n0 | \n0.008 | \n|
0 | \n1 | \n0 | \n0.817 | \n|
0 | \n1 | \n2 | \n0.037 | \n|
3 | \n12 | \n1 | \n0.112 | \n|
0 | \n3 | \n1 | \n0.664 | \n|
3 | \n3 | \n0 | \n0.004 | \n|
0 | \n1 | \n0 | \n0.074 | \n|
2 | \n3 | \n0 | \n0.003 | \n|
0 | \n0 | \n2 | \n0.817 | \n|
0 | \n3 | \n0 | \n0.515 | \n|
0 | \n1 | \n1 | \n0.372 | \n|
0 | \n4 | \n1 | \n0.648 | \n|
0 | \n2 | \n0 | \n0.655 | \n
Relationship between the isolated type of bacteria and the degree of ONJ.
Antibiograms were also performed for each of the species found, in order to guide the antibiotic pattern of these patients. We studied the six most common antibiotics, as well as the specific ones for the pathology described in the literature, we observed a variable bacterial behavior among the patients with osteonecrosis of the jaws.
\nPenicillin G did not show complete sensitivity in any patient against all the bacteria isolated in the cultures, in addition, there was much variability among patients regarding the response to this antibiotic (Figure 6).
\nRelationship between the isolated type of bacteria and the degree of ONJ.
The combination of amoxicillin and clavulanic acid showed good sensitivity in most patients (82.6%) although this was not statistically significant (Figure 7).
\nAntibiogram of Penicillin G.
Clindamycin was effective in 40% of patients and resistant in 14.5%, while 28% of the patients showed variability in the response to this antibiotic. Azithromycin was effective in a few patients (38%) and the response was highly variable, without showing complete sensitivity to isolated bacteria (Figure 8).
\nAntibiogram of the association of amoxicillin with clavulanic acid.
Clindamycin antibiogram.
Levofloxacin was effective in 42.8% of the patients, which showed good sensitivity in most cases (88.8%). Last of all, gentamicin, another antibiotic which is less frequent in our daily practice, showed good sensitivity although it was effective in few patients (38%).
\nI would like to thank to Aram Ríos for his invaluable cooperation in graphic design of the book chapter.
\nAccording to the Organ Procurement and Transplantation Network, there are currently over 110,000 patients on the waiting list for organ transplants. Over the past 50 years, therapeutic advances and improvements in surgical techniques have increased the number of patients who could survive and benefit from organ transplantation. Unfortunately, the number of organs available through donation has not changed significantly. Thus, there is a growing disparity between organ supply and demand. Although efforts to enlarge the human donor pool have improved organ availability, even a massive expansion in organ donation would not ensure that a compatible organ would be available when and where necessary for a patient in need. Therefore, other alternatives besides expanded human donation are required.
A variety of efforts are making substantial progress in addressing the lack of organs. One area of research that is rapidly approaching clinical reality is xenotransplantation, the use of animal tissues and organs to treat patients [1]. Aside from the potential for creating an unlimited supply of organs, recent advancements in genome engineering technologies allows the genetic modification of animals to produce donor organs which are less prone to rejection for xenotransplantation in human patients.
Xenotransplantation experiments were described as early as the seventeenth-century [2], with sporadic attempts made to transplant a variety of animal tissues and organs into patients throughout the nineteenth and early twentieth centuries [3, 4, 5, 6, 7]. After World War II, organ transplantation from living humans was considered too high risk, and cadaveric organs were insufficient in both quality and number to meet clinical needs. Development of immunosuppressive drugs suggested the possibility that organs from more closely-related mammals could potentially be used in humans. As a consequence, xenotransplantation efforts shifted to the use of organs from primates in human patients. In the 1960s, experiments by Reemstma et al. [8, 9], Hardy et al. [10], and Starzl et al. [11, 12] showed that while it was technically possible to transplant animal organs into humans, there were still too many clinical challenges at that time for the approach to be viable. More research was required to understand and overcome the barriers to the practical application of xenotransplantation in humans.
One of the major advances in xenotransplantation research in the past few decades has been the focus on the use of pigs as donors [13]. This was based, in part, on purely practical considerations. Unlike primates, pigs are an agricultural species for which large scale breeding is well-established. In addition, the evolutionary distance between humans and pigs reduces the risk of transmission of zoonoses from pig organs to patients compared with primate organs. Most importantly, the use of porcine organs does not present the same ethical barriers as the use of non-human primate organs [14].
Although the anatomy and physiology of pig organs is closely analogous to that of humans, the advantages of porcine organ production and availability do not address the critical issue of incompatibilities of non-human tissues and organs with the human immune system [15]. Significant advancements have been made in recent years in understanding the molecular mechanisms of xenorejection responses, and a variety of genetic modifications have been made to overcome these mechanisms. Experiments transplanting pig organs into non-human primates have demonstrated a progressive improvement in organ survival and function as new genetics and drug regimens have been implemented [16]. The FDA is currently developing guidelines for clinical xenotransplantation [17], and efforts to initiate clinical trials in the near term have been announced [18].
The immune system is designed to recognize and eliminate harmful pathogens, while remaining unresponsive to host cells and beneficial microbes. The immune system can be divided into innate and adaptive responses, an interdependent set of activities which both contribute to immunity. The innate response is more immediate, broadly recognizing conserved microbial elements, such as cell wall polysaccharides, and activating a variety of cell types which attack the invading pathogens [19]. The adaptive immune response, which is typically initiated by innate response mechanisms, leads to more precise antigen-specific antibodies and immune cells that continue to control and eliminate pathogens. In addition, the adaptive response creates long-lasting immune “memory” for rapid and specific protection against future infections, as demonstrated by vaccines [20].
Despite being described as separate systems, the innate and adaptive immune responses are highly interdependent and create a layered set of defenses with increasing specificity for pathogens over time [21]. Under normal circumstances, any individual function may not eliminate a given target with 100% efficiency, but when used together in a redundant fashion can prevent nearly all infection. Although the specificity of the immune response indirectly helps to avoid recognition of host tissues, additional tolerance mechanisms are required to restrain the immune system to prevent autoreactivity. Disruptions of the balance between immunity and tolerance can lead to the immune system destroying host tissues (autoimmunity) or allowing repeated severe infections (immunodeficiency) [22].
The transplantation of foreign cells or tissues into a human host can trigger a hostile response from the immune system, leading to immune rejection. The extraordinary precision of the immune system can distinguish even minor differences between donor and recipient, so that even organs from closely related donors may be rejected. Although immunosuppressive drugs can reduce the chance of rejection of human donor organs, the massive amount of immunogenic material found in a whole organ presents an ongoing risk which requires monitoring. Because of the greater genetic differences between pigs and humans, the vigor of the rejection response is much stronger than occurs between human donors and recipients, requiring more and different solutions.
A major advantage in using pigs for xenotransplantation is the potential to manipulate the porcine genome to create donor organs that are more compatible for human patients. However, the scope of the engineering challenge in xenotransplantation is extremely large, involving a variety of genes and pathways. With so many potential targets for genetic modification, an assortment of different genome engineering strategies have been applied, including editing or deletion of porcine genes and insertion of human or engineered genes. Because of the great diversity of genome modification efforts being carried out in xenotransplantation research, representative approaches will be highlighted here as examples of the general types of the engineering strategies being employed.
Historically, mice have been subject to more and different genetic modifications than any other mammalian species, and many of the protocols described here were first developed in mice. Aside from their well-established and convenient husbandry, small size, and rapid generation times, mice also have a variety of technological advantages for genome manipulation and production. Although genetic modification has been demonstrated for multiple agricultural species, including pigs, the scale and complexity possible with mice has, until recently, not been available for pigs [23].
One advantage for the creation of mice with multiple genetic modifications is the availability of embryonic stem (ES) cells, which can be cultured
Mouse ES cells not only allow more straightforward and efficient genome engineering, but also facilitate large scale production of cloned mice. The mouse ES cells typically employed for genetic modification can be injected into very early stage embryos (blastocysts) and will aggressively populate the inner cell mass, creating viable chimeric mice which are almost entirely ES-cell derived. Since the ES cells will also contribute to the germ cells of the chimeric mice, the progeny will be highly likely to receive the genetic modifications made to the ES cells [27]. Without readily available porcine ES cells, pig cloning instead relies upon somatic cell nuclear transfer (SCNT), similar to the protocols used to create the sheep “Dolly”. In this approach, pig oocyte nuclei are replaced with nuclei from the modified primary pig cells, and embryonic development stimulated electrochemically. The embryos are transferred to female surrogates and allowed to develop. The level of complexity and effort involved leads to lower efficiencies and higher costs for porcine SCNT relative to mouse ES cell cloning. Additionally, the size and scale of the facilities required for pig cloning is significantly greater compared with mouse cloning, further limiting availability [28].
In the following sections, different types of gene modifications are described with examples of their application in porcine genome engineering for xenotransplantation.
As mentioned above, porcine cells produce molecules which are rapidly recognized by the human immune system and rejected. One straightforward approach to engineering the pig would be to simply eliminate the genes encoding reactive genes by either disrupting or removing the coding sequence. Several of the technical routes which can be employed to accomplish this are discussed below.
Gene knockout (KO) approaches developed for use in mouse ES cells generally rely upon homologous recombination to replace a region of genomic DNA with a heterologous DNA sequence, which interrupts the function of the target gene [29]. To accomplish this, a DNA vector is generated with the heterologous DNA flanked on either side by sequences identical to regions flanking the genomic region to be eliminated. When introduced into mouse ES cells, the flanking sequences of the DNA vector first align with the cognate regions of the genome on either side of the target gene, after which the homologous recombination machinery replaces the genomic target with the heterologous DNA vector sequence found between the flanking sequences.
Because homologous recombination occurs at a relatively low rate, in order to identify properly targeted cells within the larger cell population, it is common to include a gene in the heterologous DNA to be inserted into the genome, which, once properly inserted, allows selection of the desired cells. For example, genes which confer resistance to drugs which kill mammalian cells (neomycin hygromycin or puromycin resistance), or genes encoding molecules that enable cells to be isolated via flow cytometry (green fluorescent protein or novel cell surface markers), allow isolation of even extremely rare targeted cells from a large mixed population [30].
The use of gene KO approaches was one of the earliest successes in pig genetic modification for xenotransplantation [31]. The porcine genome encodes proteins that can be substantially different from their human counterparts, or that carry additional modifications which are not present in humans and can induce immune responses. These molecules are collectively referred to as “xenoantigens” [32]. Some of the most reactive of these targets are carbohydrate molecules found as post-translational modifications to proteins observed in pig, but not human, cells. Human serum can contain high levels of pre-existing antibodies specific for these porcine-specific glycan epitopes, leading to the destruction of pig cells expressing these molecules through antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) mechanisms [33]. It is not entirely clear why human serum carries antibodies to these particular carbohydrates; one proposal is that the xenoantigens are related to glycans found in the cell walls of pathogens, others suggest that the human dietary consumption of pork causes antibody generation to the porcine-specific molecules [34]. Because the novel carbohydrate structures are created by specific glycosylation enzymes, it is possible to eliminate the gene responsible for the enzymatic activity and prevent the xenoantigen from being expressed by pig cells.
The GGTA1 gene encodes the enzyme responsible for creating the highly reactive glycan Gal alpha (1,3) Gal epitope in pigs [35]. The KO of the GGTA1 gene is one of the earliest genetic modifications of pigs for application in xenotransplantation, and resulted in greatly reduced human antibody recognition of porcine cells [36, 37]. However, ablation of the GGTA1 gene alone did not completely eliminate porcine cell recognition by human serum antibodies. The enzymes responsible for other xenoantigens, such as CMAH (cytidine monophosphate-N-acetylneuraminic acid hydroxylase critical for Neu5Gc biosynthesis) and B4GALNT2 (beta 1,4 N-acetylgalactosaminyltransferase), have been identified as sources of porcine-specific epitopes bound by antibodies found in human serum. In each case, the deletion of the gene responsible for creating the specific glycan leads to greatly decreased recognition of porcine cells by antibodies in human serum, and reduction in complement-mediated destruction [38, 39].
Another subset of xenoantigens is the swine leukocyte antigens (SLA), the physical and functional equivalent of the human leukocyte antigens (HLA) [40]. Much like the case for human HLA, the SLA genes are highly diverse and individual patients will have a variable level of cross-reactive antibodies in their serum for a given set of SLA genes [41]. Although typing of patients and porcine donors to find the best HLA-SLA matches would be similar to the current system used for determining allotransplant cross-reactivity [42], use of gene targeting or editing technologies could easily eliminate the genes encoding SLA entirely. However, unlike the glycan epitopes described above, the SLA have a critical role in antigen presentation as part of the immune response, and thus the deletion of SLA could create risks of immune deficiencies that outweigh their risks as xenoantigens. Instead, alternate approaches seek to create engineered SLA proteins lacking the epitopes responsible for the immunogenicity while maintaining their antigen presentation functions [43].
The ease and efficiency of creating gene KO has improved recently through the use of engineered molecules to create genome disruptions in a process referred to as “gene editing”. These novel molecules can be designed to generate double-strand DNA breaks at virtually any chosen genomic site
The most prominent of these novel tools for gene editing are Zinc Finger Nucleases (ZFN), Transcription Activator-Like Effector Nuclease (TALEN) and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), each of which consists of two regions: a sequence-specific DNA binding domain and an enzymatic function that creates a double-strand break in the target DNA [45, 46, 47]. For ZFN and TALEN, the synthetic DNA binding domain is created by repetitive protein modules which can be joined combinatorially to recognize a particular DNA sequence. Both approaches, while successful, require a significant investment of time and resources to identify functional molecules. CRISPR, like ZFN and TALEN, has the ability to generate double-strand DNA breaks, however, the DNA binding domain relies upon RNA base-pairing with target DNA for its precision. The use of an RNA to guide specificity greatly improves the speed and efficiency in identifying optimal molecules at a much lower cost, which has led to its rapid adoption in genome engineering [48, 49].
The use of CRISPR for the rapid modification of the pig genome was recently demonstrated with the ablation of porcine endogenous retroviral (PERV) sequences. The pig genome carries 25 or more copies of these gamma retroviral sequences, which are transmitted from parent to offspring through inheritance. Application of CRISPR was able to eliminate the PERV sequences from the genome of porcine cells [50]. Although the potential risk of infectious disease from porcine organs caused by PERV sequences in xenotransplantation is debatable, the results show the ability of CRISPR to target multiple, homologous loci throughout the genome. A key question that has arisen regarding large scale CRISPR targeting at multiple genomic sites is whether significant numbers of off-target double-stranded breaks were introduced, which may create unexpected mutations in the resulting pigs [51]. Nonetheless, the ease of use of CRISPR has resulted in widespread adoption for genome engineering in xenotransplantation.
Gene deletion has been instrumental in the advancement of xenotransplantation, however, there are limitations to its application; the genes of interest must be non-essential to pig viability, development, fertility and, most importantly, organ function. The number of distinct loci to be targeted is also a serious consideration, since independently-assorting alleles will be challenging to breed together in a reasonable timeframe. To address these concerns, additional engineering strategies are required as discussed below.
Gene KO and editing techniques have been used for ablation of xenoantigen genes but do not address the need to express human or synthetic genes in pig cells and organs. Unlike gene deletions, gene insertions require heterologous DNA to be introduced into the genome in a manner that allows subsequent expression of the gene(s) encoded by the inserted DNA. Because they are being transferred into the genome from another source, these novel genes are referred to as “transgenes” (TG), whether they are derived from natural or synthetic sequences. The general approaches to introduce TG into the genome are detailed below.
One of the earliest types of genetic modification described in mammals was insertion of DNA into the target genome by random integration. After transfection of DNA into nearly all mammalian cells, some portion of the heterologous DNA can be found incorporated at random sites in the genome [52]. The precise process for this is unclear, but presumably is a result of aberrant repair mechanisms. One hypothesis is that endogenous NHEJ machinery recognizes breaks in the genome and fortuitously utilizes the relatively higher concentration of the heterologous DNA vector sequences to repair the break [53], resulting in the insertion of the TG into the genome.
Agricultural species, including pig, were some of the earliest TG animals described, establishing the utility of this approach [54]. For xenotransplantation, several of the initial TG approaches focused on inhibiting human antibody-mediated damage of porcine organs. The binding of human antibodies to porcine cells leads to complement pathway activation and subsequent cell ablation [55]. The complement function is controlled by several proteins, such as CD46, CD55 and CD59, referred to as complement regulatory proteins (CRPs). The CRPs are broadly expressed on many different cell types to prevent harm from complement activity by raising the threshold of antibody binding required for complement pathway induction [56]. The transgenic expression of human CRPs in pigs appears to overcome human complement activity, and may have the potential to reduce, or even eliminate, the need for xenoantigen KOs. By placing the human CRP TGs under the control of strong gene expression elements, the CRP protein levels on the porcine cells can be much higher than CRP levels on normal human cells, further increasing resistance to complement-mediated destruction [57].
Pig lineages developed by multiple labs have been engineered to express human CRPs, individually or in combination. In most cases, the porcine cells appeared to be more resistant to complement-mediated destruction, and organs from TG animals survived longer in xenotransplant experiments in non-human primates [58, 59, 60]. Because each of the CRPs control a different part of the complement pathway, the use of multiple human TGs was more effective in protecting cells from complement-mediated destruction than individual TGs [61]. Together with the removal of key xenoantigens, the expression of human CRPs by porcine cells has greatly reduced the effects of human serum antibodies on xenografts.
Because random insertion of DNA does not require homologous recombination, it is relatively rapid and efficient to produce transgenic animals [62]. The process is so efficient that the selection methods that are critical for gene KO described above are often unnecessary for TG. Despite the speed and ease of generation, random integration of TGs has several drawbacks. Variabilities in genome structure can affect the expression level of genes inserted at distinct chromosomal regions, such that identical TGs may express at very different levels depending upon their specific location [63]. Furthermore, multiple copies of a given TG may be inserted into the genome at a single site, creating concatenated repeats which can be unstable and yield variable expression levels [64]. Random TG insertion may occur within or near endogenous genes and alter or inactivate their function, leading to tumorigenesis, instability or even lethality [65].
The development of techniques for precise gene KO by homologous recombination has been adapted for site-specific gene insertion or gene knock-in (KI). Similar to the KO vectors described above, the gene to be introduced is flanked by DNA sequences that are identical to regions of the genome to be targeted. After introduction of the heterologous DNA vector, the regions of DNA sequence identity are aligned with the target genome sequence, after which the homologous recombination machinery catalyzes reactions which swap the endogenous genomic DNA with the heterologous DNA within the construct. If the recombination event occurs with high fidelity, the gene of interest will functionally replace the gene that was removed [24]. Similar to gene KO, this approach is much less efficient than random TG integration. Therefore, vectors carrying the TG are often designed to incorporate selectable markers, similar to those used for gene KO, to allow the identification of cells carrying the desired TG in the genome. In this case, both targeted and randomly integrated TGs may be selected, requiring additional assays, such as PCR or Southern blotting, to distinguish between sequence-specific and random insertion events [30].
As described above for gene KO, specific targeting is more efficient in murine ES cells, which express the enzymatic machinery necessary for homologous recombination, than is currently possible for pig primary cells. Insertion of heterologous DNA into the mammalian genome is believed to be driven by endogenous DNA repair mechanisms, presumably in response to DNA breaks, whether randomly via NHEJ, or specifically via homologous recombination [66]. The deliberate introduction of double-stranded DNA breaks at the desired integration site should therefore improve the efficiency of heterologous DNA insertion by activating and recruiting the cellular repair machinery. Application of ZFN, TALEN and CRISPR technologies have shown that homologous recombination efficiencies are improved when one or more double-strand DNA breaks are introduced into the genome at the desired site of insertion [67] with CRISPR exhibiting bi-allelic targeting rates as high as 90% [68]. The use of these more advanced genome engineering tools has greatly improved the rates and specificity of both gene deletion and gene insertion in genomes.
Gene insertion by homologous recombination for xenotransplantation has not advanced as rapidly as other approaches, in part due to the challenges of using primary porcine cells, for which the efficiencies can be extremely low, particularly with large DNA constructs. Use of improved genome engineering tools with increased targeting efficiencies have already been applied in pig and will continue to grow in impact [69]. However, even with improved efficiencies of gene insertion, breeding pigs with multiple, independently segregating loci is challenging. The number of litters required to produce animals bearing all of the genetic modifications greatly increases with each additional locus, which can be impractical for large animals such as pigs. Therefore, the ability to insert the maximal amount of genetic information into the genome in the minimal number of steps, as discussed below, is highly valuable.
The most straightforward example of multigenic targeting at a single site takes advantage of the observation that multiple DNA vectors co-transfected into cells will tend to insert together at a given genome site. This approach was used successfully to simultaneously introduce as many as five large transgenes in a single step into porcine cells [70]. Although difficulties in producing mature cloned pigs limited the study to animals with fewer integrated genes, the study demonstrated the feasibility of rapidly making animals with multiple TG.
Another, relatively less complicated, way to introduce multiple TG is to generate large DNA constructs bearing multiple TGs for integration at random into the genome [71]. This greatly reduces the complexity of screening, while increasing the efficiency of insertion, but still relies upon random integrants which can have variable TG copy numbers and expression levels.
Multiple genomic regions have been defined, such as Rosa26, which allow expression of heterologous genes at similar levels regardless of cell type. These “safe harbor” regions are believed to have a chromatin structure that is more easily accessible to the gene expression machinery, regardless of cell type. Targeting at porcine homologs of murine safe harbor sites such as Rosa26 has been described and demonstrates the utility of this approach [70, 72]. On a practical level, the use of safe harbor sites yields more reproducible gene expression than random TG insertions, so fewer lineages are required to select animals with desired TG levels. Furthermore, the defined location and copy number of TG inserted at a safe harbor site makes breeding and genotyping more straightforward, and is expected to provide a less complicated regulatory pathway for clinical use.
As DNA synthesis and assembly has improved, increasingly large DNA constructs encoding a variety of TG are possible, however, as the size of the DNA increases, the rate of insertion decreases. Considering the lower insertion rates observed for large animals such as pig, alternate approaches are necessary to incorporate larger DNAs into the genome.
Bacteriophage- and yeast-derived site-specific recombinases are, as the name suggests, proteins which catalyze recombination between two specific DNA recognition sites, small (<50 base pair) sequences that are unique to the recombinase being used. The recombination event is highly efficient, in some cases eliminating the need for selection genes, and allowing large DNA constructs to be inserted at a much higher frequency than possible for homologous recombination [73].
One limitation for the use of site-specific recombination is the need for a recognition sequence to be present in the target genome at the desired locus. This requires a preceding step in which the recognition site is engineered into the genome using less efficient homologous recombination. Therefore, the gain in efficiency for introduction of large DNA constructs may be offset by the need for insertion of the recombinase recognition site into the genome. Despite this constraint, the potential for site-specific recombination into a defined locus has been demonstrated in pigs [70] and provides a route for more rapid complex genetic modifications.
The advancements in genome engineering, both in general and in their application to xenotransplantation, have been significant, but many needs remain to be addressed. As new genome engineering tools are identified and further refined, improvement of targeting efficiencies will allow more sophisticated modifications of the pig genome. Ideally, the pig genome will become as readily manipulated as the mouse, allowing researchers to further leverage approaches shown to be effective in murine models.
One major technological difference in the genetic modification of mice and pigs (and many other mammalian species) is the lack of ES cells possessing significant rates of homologous recombination that can be grown in culture for extended periods and subjected to multiple manipulations without losing the ability to produce viable pigs. Efforts to identify natural or induced pluripotent stem cells (iPSC) suitable for these purposes have been described, but have yet to demonstrate practical application for porcine genome engineering [74]. Ongoing work will be required to identify and validate cells which meet these needs.
The function of the TGs themselves can also be further improved. The majority of TG constructs used in pigs have used constitutive promoters to drive high level expression of the proteins encoded by the TGs. In some cases, such as CRPs, this approach may be useful, however, overexpression of TGs which inhibit critical immune processes may create risks of immune deficiency and infections. For this reason, use of expression control elements which can turn on and off TG activity is of increasing interest in xenotransplantation. There are multiple examples of inducible promoters employed in mice which can be controlled by exogenously applied small molecules (such as the tetracycline repressor system), or by endogenous signals (such as promoters for innate immune response genes) [75]. Advanced DNA synthesis and assembly methods also allow synthetic biology approaches to create novel signaling pathways and networks not present in nature.
Immune tolerance is another very active area in xenotransplantation research. As the molecular mechanisms controlling the balance between immunity and tolerance are further elucidated, manipulation of the human immune system itself to specifically reduce or eliminate responses to porcine targets, while leaving intact immunity to infectious diseases, will help overcome xenorejection. Multiple approaches are currently being tested and genome targets identified to encourage human immune tolerance of porcine cells and tissues [76, 77].
The speed and ease of genome engineering technologies has helped to overcome many of the limitations for the use of pig organs for xenotransplantation. Despite recent achievements, a key question remains: which combination of genetic modifications is most critical to make a pig organ useful for xenotransplantation? Ongoing experiments seek to address this question, but the answers are likely to be complex and dependent upon the type of organ, the specific immune mechanisms involved, and perhaps other factors that are not yet defined. It is very likely that the first set of genetic modifications of pigs used for xenotransplantation in humans will not be the final set, as the understanding of the mechanisms of xenorejection increases and better strategies developed to influence the human immune response. Continuing progress in genome engineering technologies of pigs will allow the creation of the more complex modifications necessary to meet these demands. Although much remains to be done, it is clear that given the current rate of progress, overcoming the crisis of human organ shortage with unlimited rejection-free porcine organs is rapidly growing closer to reality.
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