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",isbn:"978-1-83969-588-9",printIsbn:"978-1-83969-587-2",pdfIsbn:"978-1-83969-589-6",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"543783652b9092962a8fa4bed38eeb17",bookSignature:"Dr. Hamadttu El-Shafie",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10739.jpg",keywords:"Pollinators, Decomposers, Agricultural Intensification, Pesticides Application, Global Warming, Insect Fauna, Invasive Species, Native Species, Deforestation, Destruction of Insect Habitats, Botanical Insecticides, Biodiversity",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 25th 2021",dateEndSecondStepPublish:"March 25th 2021",dateEndThirdStepPublish:"May 24th 2021",dateEndFourthStepPublish:"August 12th 2021",dateEndFifthStepPublish:"October 11th 2021",remainingDaysToSecondStep:"19 days",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Associate Professor of entomology, appointed head of Department of Crop protection, then deputy dean of academic affairs, Faculty of Agriculture, University of Khartoum. At the moment he is the head of the red palm weevil research program, King Faisal University.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"192142",title:"Dr.",name:"Hamadttu",middleName:null,surname:"El-Shafie",slug:"hamadttu-el-shafie",fullName:"Hamadttu El-Shafie",profilePictureURL:"https://mts.intechopen.com/storage/users/192142/images/system/192142.jpg",biography:"Hamadttu Abdel Farag El-Shafie is an associate professor of entomology and senior research entomologist at the Date Palm Research Center of Excellence, King Faisal University, Saudi Arabia. He is the head of IPM research program in date palm. El-Shafie obtained his B.Sc. and M.Sc. degrees from the University of Khartoum, Sudan in 1988 and 1993, respectively. He received his Ph.D. degree from University of Giessen, Germany in 2001. He was appointed head of Crop Protection Department at University of Khartoum in 2008, and then deputy dean for academic affairs at Faculty of Agriculture, University of Khartoum. He supervised 25 M.Sc. students and 5 Ph.D. students at University of Khartoum. His research interest focuses on management of field crop pests using neem biopesticides, and biology and ecology of date palm pests including mites. He also has interest in control of red palm weevil using semiochemicals. He published 60 research papers in international peer-reviewed journals and 10 book chapters with international publishers such as Springer, John Wiley and IntechOpen, in addition to more than 25 international conferences in the field of entomology. 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From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"56408",title:"Periodontal Considerations in Adult Orthodontic Patients",doi:"10.5772/intechopen.69960",slug:"periodontal-considerations-in-adult-orthodontic-patients",body:'\nOver the past three decades, the number of adult orthodontic patients has increased markedly. Recent surveys have reported that orthodontic treatment contributes to significant improvements in both professional and personal life, especially in adult patients who generally have undergone substantial loss of sustaining tissues, resulting in compromised function and aesthetics. Based on the new-found self-confidence, the majority of these patients suggest orthodontic treatment to friends and relatives. Therefore, orthodontic treatment seems to be a promising emerging therapy to be integrated into a multidisciplinary dental treatment approach.
\nApart from establishing a functional occlusion and improving dental and facial aesthetics, one of the major objectives of orthodontic therapy is enhancement and maintenance of periodontal health. In adult patients, the altered periodontal health might result in teeth loss, altered function and compromised aesthetics. Most of these patients present a variety of problems, which include teeth overeruption, migration, traumatic occlusion, irregular interdental spacing, consumed occlusal surfaces, irregular occlusal planes and loss of vertical dimension. In such complex and challenging clinical situations, an interdisciplinary treatment is mandatory. Unfortunately, in everyday orthodontic practice, insufficient emphasis is placed on comprehensive diagnosis prior to orthodontic therapy with particular attention to periodontal health and to its control and maintenance throughout the therapy. All attempts of limited treatment, with poor consideration of the whole picture will result in failure, relapse and very often aggravation of the pathology. The careful control of periodontal pathologies before, during and after orthodontic treatment, along with functional rehabilitation and patient’s compliance can provide the most satisfactory results and long-term stability.
\nWe present herein our step-by-step approach on pre-orthodontic and orthodontic treatment of periodontally compromised patients, through several detailed clinical cases and clear scientific protocols. Moreover, we consider several important issues concerning the bidirectional interaction of orthodontics and periodontology and discuss ways to optimize it. Potentials and limitations of such interaction are reflected. Furthermore, we summarize scientific evidence and clinical expertise on different techniques aiming enhancement and acceleration of adult orthodontic therapy, leading to conclusions of high relevance in terms of an effective and efficient therapy.
\nGuided by sound scientific principles and constructive clinical experience, it is vitally important to keep in mind that adult patients with orthodontic needs require individualized and tailored treatment plans to meet both clinical success and patient’s expectations. The information presented in this chapter is gathered by considering these aspects and with the hope of providing investigators and clinicians with solid bases for the state of art and potential future directions of interdisciplinary treatments.
\nAs all medical treatments, dental therapies might have two approaches, which are referred to as ‘causal’ and ‘symptomatic’. It is of utmost importance that when possible, these approaches are considered complementary, not as an alternative to each other. Therefore, in all cases when causal factors can be identified, the treatment should focus on addressing them first. If these approaches are followed, the symptomatic spectrum might be easier to treat or even disappear.
\nIn oral-related pathologies, many etiological factors are recognized and widely accepted, whereas sometimes their precise effects and multifactorial influences are difficult to quantify. Nevertheless, the identification of potential causal factors is the fundamental part of any diagnostic process and should be performed through an accurate clinical visit.
\nIn case of particular malocclusions, such as severe deep bite or crowding, the direct causative relationships and influences on periodontal health are evident. Such influences are determined primarily by the pathological traumatic occlusion and unfavourable position of the tooth inside the bone envelope, and secondarily, by favouring the plaque accumulation which results in progression of plaque-induced periodontal breakdown.
\nThis is not always the case for periodontal pathologies that trigger or predispose orthodontic problems. In the absence of a thorough clinical check and comprehensive causal diagnosis, numerous orthodontic symptoms might be wrongly treated without accounting for the underlying periodontal, often causative or predisposing factor. Such a situation is typically encountered in adult patient referring diastemas opening over time and teeth flaring (Figure 1a). If no detailed clinical and radiographic checks were performed, neglecting the periodontal health, the orthodontic treatment alone would have aggravated the periodontal state, resulting in an iatrogenic damage and the post-treatment stability would have been questionable.
\nTwenty-eight-year-old female patient (FG), whose major requirement is diastema closure and teeth alignment. (a) Intraoral aspect; (b) during periodontal probing, it is noticed the presence of infrabony defects in multiple sites on both maxilla and mandible. A complete series of periapical radiographs is performed, showing a diffuse bone loss. (c) Bacteriological analysis on collected gingival cervicular fluid indicated high levels of actinobacillus actinomycetemcomitans, porphyromonas gingivalis and prevotella intermedia.
The clinical check-up itself should always be preceded by a detailed anamnesis for identification of potential risk factors. Thereafter, it should include compilation of a periodontal chart including all relevant periodontal indexes, general radiographic estimation and, when deemed necessary, a detailed radiographic assessment through series of periapical radiographs (Figure 1b).
\nIt is of utmost importance to consider the presence of highly compromised periodontal health in young patients as an indicator that might suggests need for further laboratory and genetic analysis in order to identify potential risk factors to periodontal pathology or important systemic pathologies (Figure 1c).
\nIn terms of ethology, it is well established that periodontitis is a multifactorial condition and apart from microbial and environmental factors, its progression is determined also by genetic susceptibility [1]. Epidemiologic data suggest that approximately 10–15% of populations are susceptible to a quick progression from gingivitis to periodontitis which can hardly be explained by solely microbiological or external factors [2, 3]. Numerous genetic polymorphisms have been characterized and recognized to play a role here [4]. While the influence of genomic testing on non-surgical periodontal treatment outcomes has been recently questioned [5], it should be kept in mind that its consideration remains highly important for prevention measures, early diagnosis and better individualized treatment protocol. Moreover, when integrated into a multifactorial diagnostic scheme, it allows for a comprehensive estimation of risk factors. To-date epidemiological evidence is limited and further investigation is required in order to thoroughly understand the nature of this association and its clinical implications [3]. Nevertheless, since full genome sequencing is feasible, phenotypic and genotypic data can be used to improve ‘personalized’ treatment and public oral health [6]. Apart from genetic influences, other risk factors such as diabetes, smoking and stress should also be considered, controlled and integrated into the overall treatment plan. The destructive effects of smoking on periodontal tissues have long been recognized, and recent biochemical and genetic studies have clarified direct and indirect pathways of this association [7, 8]. Levels of matrix metalloproteinase-8 (MMP-8), which is involved in periodontal destructions, are significantly increased in smoking patients. Additionally, immune response is modified and the pathogenesis of the disease is negatively affected [8]. A similar pattern is present in patients affected by type 2 diabetes mellitus suggesting that diabetic-smoker patients have increased periodontal breakdown and are prone to a more severe periodontitis [9].
\nOral functional and aesthetic rehabilitation in adult patients is a complex process that requires exhaustive scientific knowledge, extensive clinical experience and, in most cases, a multidisciplinary treatment planning. Independently of what the role of orthodontic therapy might be in the multidisciplinary frame, each tooth movement should initiate and be fulfilled in the presence of a healthy periodontium. It has already been demonstrated that if orthodontic treatment is conducted in the presence of periodontitis, it causes major bone destruction and clinical attachment loss (Figure 2a, b).
\nTwenty-two-year-old female patient having a fixed orthodontic appliance for 2 years. She was referred to us by an orthodontist who after one year of orthodontic therapy realised the gravity of the periodontal situation after performing a panoramic radiograph. The orthodontist refused to remove the orthodontic appliance, afraid that the patient would lose the teeth, being retained in their position only through the ligation to the archwire. (a) Panoramic radiograph showing the extensive bone loss in almost all maxillary teeth. (b) Periapical radiographs indicating the almost complete loss of periodontal support for multiple maxillary teeth.
General treatment guidelines for orthodontic patients with chronic periodontitis suggest initial non-surgical therapy for adequate plaque control and then revaluation [10]. It is purported that critical pocket depth for maintaining periodontal health with no need for surgical intervention is 4–5 mm, but this should be carefully estimated considering patient compliance on adequate oral hygiene and specific needs for regenerative therapy [11].
\nThe non-surgical periodontal treatment consisting of scaling a root planning results in gingival recession due to inflammation reduction (Figure 3a). It is advisable to inform the patient in advance regarding this effect as it might compromise aesthetics. Following the classical approach, in case of persistence of infrabony defects of 4–5 mm deep after the initial periodontal therapy, the open flap debridement and regenerative treatment are carried out (Figure 3b–e). Another more recent alternative approach at this stage is the performance of deep debridement and regeneration in a unique phase intra-surgically proceeded only by superficial debridement in order to avoid gingival recession and to have the possibility to reposition the soft tissues more coronally. This would allow for unaltered aesthetics and better root coverage, especially considering the fact that flap adaption is a crucial aspect of the healing quality (Figures 4a–g and 5a–g). Despite the preferred approach, the surgical stage should be followed by a healing time before orthodontic therapy commencement. This period would allow for connective tissue stabilization and remodelling, restoration of health and evaluation of patient’s compliance [12]. If the regenerative therapy is integrated into an ongoing orthodontic treatment, the compromised teeth should be immobilized through rigid splinting in order to stabilize the clot and the regenerative material throughout the healing phase.
\nPatient F.G. (a) Intraoral aspect 2 weeks after completion of periodontal causal therapy (scaling and root planing). Notice the gingival recession that follows the reduction of inflammation; (b, c) open flap debridement on vestibular and palatal side; (d) injection of enamel matrix derivatives; (e, f) flap adaptation and suturing on the maxillary and mandibular arch. Because of the post-periodontal therapy recession, the flap adaptation results more challenging; (g) orthodontic therapy during space closure phase; (h) panoramic radiograph before periodontal therapy; (i) panoramic radiograph during orthodontic therapy. Please notice the overall enhancement of bone level and reduction of infrabony defects. (j, k, l) intraoral aspects at the day of orthodontic appliance removal. The patient showed great compliance during the entire treatment.
Thirty-eight-year-old female patient (T.A.), whose midline diastema was opened during the past 3 years. Major request was diastema closure. (a) Initial intraoral aspect; (b) initial radiograph; (c) deep manual debridement during surgical intervention. A supragingival debridement was previously performed; (d) sufficient gingival tissue for appropriate coverage of regenerative materials; (e) synthetic bone grafting; (f) membrane shaped extraorally following the area to be covered; (g) adaptation of the membrane in order to cover all grafting material; (h) suturing with coronal flap adaptation; (i) orthodontic treatment started 3 months after surgery; (j) clinical aspect at the end of orthodontic treatment; (k) radiograph at the end of orthodontic treatment with lingual fixed retainer.
(a) Gingivitis present during orthodontic therapy. (b) when the inflammation is limited only at the gingival level and the deep periodontal tissue is not compromised, after orthodontic appliance removal the gingival inflammation disappears. (c) Periodontal probing after orthodontic appliance removal indicates healthy periodontal state.
The regenerative therapy might follow several approaches, including open flap debridement, guided tissue regeneration (GTR) associated or not with different types of bone grafting, growth factors and more recently also stem cell-based therapy [13–15]. Utilization of mesenchymal stem cells in periodontal regenerative therapy has already resulted in promising outcomes that need to be further elucidated especially in terms of cell survival and efficient expression of programmed proliferative capacity to consent fully translation of mesenchymal stem cell-based therapy into clinical practice [15–22]. Irrespective of the chosen regenerative approach, the orthodontic treatment that follows should aim for elimination of occlusal traumatic contacts and establishment of a functional occlusion, which is one of the major factors for maintenance of periodontal health. Dental implant therapy for tooth replacement is incorporated after a thorough treatment planning followed by the positioning of teeth and roots into correct positions. If implants are planned and inserted before the end of orthodontic therapy, they might also be used as an anchorage unit for facilitating the orthodontic treatment. Maintenance of periodontal health is of utmost importance also for implants success and survival. Patients susceptible to periodontal pathologies are more prone to peri-implant inflammation and implant failure. Potential prosthetic restorations are usually performed at the end of orthodontic therapy, aiming reconstruction of lost tooth tissues or replacement of missing crowns.
\nMost of adult patients suffer also from enamel and dentine excessive consumption especially at the cervical area, which results in highly compromised aesthetics, hypersensitivity and important discomfort [23, 24]. Treatment of these cervical, non-carious defects is mainly focused on hypersensitivity reduction [25], whereas hard tissue reconstruction remains a controversial and challenging issue, especially considering the aetiology and progress of such pathology. Recent emerging technologies have proposed restoration of dental enamel using high repetition rate femtosecond lasers and novel iron-doped calcium phosphate biomaterials. During this procedure, the irradiated mineral transforms into a densified layer of acid-resistant ion-doped β-pyrophosphate, which bonds with enamel and dentine surface of non-carious lesions [26, 27]. This promising technology is yet to be fully developed for optimal clinical usage.
\nAttempts in reducing duration of orthodontic treatment especially in adult patients have recently resulted in therapies combining surgical and non-surgical approaches to orthodontics. Even if surgical adjunctive therapies have been studied for many decades, their overall benefit is still questionable, whereas non-surgical approaches do not provide solid scientific bases for incorporation into everyday clinical practice [28, 29]. Careful consideration of patient-centred aspects, treatment time and overall cost-benefits must be performed for a thorough estimation of these approaches.
\nEach adult patient is a challenging situation that in the majority of cases requires the periodontal and orthodontic therapy for denture preparation and later prosthetic therapy for full rehabilitation. In almost all cases of mature patients, orthodontic treatment alone would not result in the best possible approach for oral functional and aesthetic rehabilitation and sometimes it would also deteriorate the overall state of oral health.
\nIt should be bared in mind that all orthodontic movements are guided by a periodontal dimension that should be of primary consideration during treatment planning and application of orthodontic biomechanics. On the other hand, correct functional occlusion and ideal tooth position are one of the major prerequisites for maintenance of periodontal health.
\nThe presence of healthy periodontal tissues is of vital importance for undertaking any kind of orthodontic or prosthetic therapy. In adult patients, even if periodontal tissues might be reduced and have compromised sustaining capacity, they should be free of inflammation. All attempts in applying an orthodontic treatment on inflamed periodontal tissues will aggravate the periodontal state and result in an iatrogenic damage [30].
\nComponents of orthodontic appliances predispose aggregation of bacterial plaque which, if not properly controlled through accurate hygiene regimen, might trigger gingivitis or its conversion into periodontitis [31, 32]. On the other hand, when a thorough oral hygiene regimen is applied, gingivitis is easily controlled, and when no other periodontal tissues get involved, it seems to disappear in long term after appliance removal (Figure 5) [12, 33]. Periodontal short-term effects after orthodontic therapy remain controversial [34], which suggest that in all cases orthodontic patients are at a higher risk for periodontal disease development. The increasing demand for orthodontic treatment and the occurrence of biofilm-related complications has positioned orthodontic treatment as a potential public health threat [35].
\nIndependent of whether the periodontal health is compromised or not, in all adult patients, particular attention should be paid to avoid when possible bulk elements such as bands or other orthodontic components placed close to gingival margin that apart from plaque retention might cause marginal gingival injury and attachment loss. In this respect, orthodontic treatments based on removable appliances or aligners permit unimpeded oral hygiene and result in better periodontal health [36]. Nonetheless, while these aligners behave superiorly in terms of oral hygiene maintenance and periodontal health, other important considerations, such as occlusal interferences, gnathologic effects and postural ones, must be made before applying them.
\nAccording to the ‘bone envelope’ theory, orthodontic tooth movement should be performed within an anatomically and functionally periodontal limited space which is in any case to be respected in order to obtain the desired movement. If the periodontal space is violated, its connective tissue might react through a series of mechanisms such as bone dehiscence and fenestration, gingival inflammation and gingival recession. Apical migration of the gingiva (gingival recession) has an unpleasant effect in both aesthetics and cervical dentinal hypersensitivity. It might be caused by periodontitis, gingival trauma and specific anatomical conditions such as tooth crowding or muscular inserts. It has been demonstrated that in cases of tooth movement beyond the ‘alveolar envelope’ such as uncontrolled orthodontic movement, the recession might arise immediately but also years after, resulting in unpleasant post-treatment effects [37, 38]. It has been reported that factors related to the development or progression of recessions in adult patients are the presence of pre-treatment recessions, thin gingival biotype, reduced width of keratinized gingiva and visual gingival inflammation [39]. Other features, such as gingival margin thickness smaller than 0.5 mm and vestibular incisor inclination (over 95°), have also been associated with higher incidence and severity of recession [40]. In cases of pre-existing recessions, it is recommended that mucogingival interceptive surgery be accomplished before orthodontic therapy to maintain the width of keratinized gingiva in the long term [41].
\nEvery orthodontic movement induces remodelling and reorganization of periodontal tissues. It is demonstrated that light and continuous forces illicit non-destructive periodontal turnover, whereas heavy forces might result in necrotic periodontal tissue and further irreversible periodontal damage. Another consequence of these uncontrolled and heavy forces might be the root resorption, which is of extreme importance in teeth with reduced periodontium as further loss of periodontal support results in increased crown-root ratio and in compromised stability and aesthetics. Peculiar control of force levels has been outlined especially for orthodontic intrusion where the surface of force application is reduced. Intrusion also requires absolute control of inflammation and bacterial biofilms in order to avoid any aggravation or creation of infrabony defect and loss of attachment [42–45].
\nIn most adult patients, the already-compromised periodontal tissue would need particular care in order to avoid further destruction and when possible aim for periodontal health enhancement.
\nProfessional cleaning and examination of periodontal tissues should be performed routinely during the entire orthodontic treatment, following a personalized schedule that is determined by the individual risk factors and the specific treatment plan.
\nIn all cases, orthodontic treatment should be suspended if patient fails to comply in maintaining the appropriate level of oral hygiene.
\nOrthodontic therapy on adult patients has become particularly popular in the last few decades, following the general trend of the modern life where overall aesthetic enhancement has become one of the major priorities. However, orthodontic treatment as a corrective tool that eliminates pathologic migration of teeth on periodontally compromised patients had been suggested long time ago in the literature, by authors such as Neustadt [46] Dummett [47] and Scoop [48]. Later studies conducted principally on animal models confirmed the beneficial effect of orthodontic therapy on periodontal health. The results of these animal studies demonstrated that movements of teeth with infrabony defects in an inflammation-free environment result in elimination of the bone defect through creation of a long epithelial junction [49, 50].
\nExtrapolation of animal studies’ findings to human conditions has been questioned, mostly because of the specific pattern of attachment loss that occurs on humans [51]. However, it is well established that in the absence of periodontal inflammation, the biological process of bone resorption and apposition during orthodontic tooth movement might positively influence the healing of periodontal defects. Similarly, the positioning of teeth into correct occlusal relations, which allow for axial and physiological distribution of masticatory forces, results in reduced stress to periodontal tissues. Moreover, such an occlusal stability contributes in diminishing mesial migration of posterior teeth and related consequences such as incorrect interdental contact points, flaring of incisor teeth and diastema opening. All these clinical symptoms are typical in adult patients, in which the malocclusion is aggravated by chronic periodontitis, resulting in the establishment of a vicious cycle where the two pathologies contribute to the exacerbation of each other (Figure 6). If the therapeutic approach does not account for both pathologies and does not follow a correct protocol starting with periodontal therapy and stabilization, the final result and its maintenance are highly questionable.
\n(a–e) The periodontal pathology has contributed in aggravating the malocclusion, characterized mainly by mesial tipping of posterior teeth, incisors flaring and diastema opening; (f–h) open flap debridement and regeneration; (i, j) soft tissue adaptation and suturing; (k) orthodontic therapy performed on a reduced periodontal tissue but with no active inflammation; (l) set of periapical radiographs after orthodontic alignment.
The orthodontic therapy can contribute to the improvement of periodontal health through reduction of intraosseous defects or furcation lesions [52–56]. It can also help in reducing gingival recession, levelling uneven gingival margins or rebuilding missing interdental papilla [12, 57, 58].
\nHowever, as reported by several recent systematic reviews, despite the major interest in trying to understand the beneficial effect of orthodontic therapy on periodontal health, the orthodontic scientific evidence still leaks solid protocols in this field and human studies are poor both qualitatively and quantitatively [44, 45, 54].
\nPreservation of final orthodontic result is often considered as the third phase of overall orthodontic therapy and its major long-term goal. Post-orthodontic relapse has been mainly attributed to elasticity of gingival tissues that are compressed towards the direction of tooth movement. Considering this, the suggested retention period should exceed the time for remodelling of periodontal fibres, which usually ranges from 4 to 6 months [59, 60]. In order to enhance post-treatment stability attributed to soft periodontal fibres, many authors have suggested adjunctive interventions such as overcorrection, interproximal reduction or circumferential fibrotomy of supracrestal gingival fibres [61]. The variety of retainers is represented by the two big categories of fixed and removable ones. Scientific data report controversial opinions regarding the retentive method of choice for patients with reduced periodontal support. While the fixed retainer assures firm position and satisfying long-term stability, it does not allow for teeth to retain their physiological mobility, and in most cases, it impedes maintenance of good oral hygiene which is of fundamental importance for these patients [62]. In all cases, bulk fixed retentions that block easy access through interdental spaces should be avoided and patients should be given exhaustive instructions for appropriate oral hygiene maintenance (Figure 7).
\n(a, b) Bulk lingual and vestibular splinting of teeth, which do not allow for appropriate oral hygiene maintenance. (c) Radiographic image showing the complete loss of periodontal support.
Finally, despite the importance of considering all periodontal and mechanical features of retentive devices, the authors of the present manuscript consider of primarily importance for long term retention a final orthodontic result that assures occlusal stability, meaning correct teeth positioning, physiological movement with no interferences or dislocating pre-contacts [63]. It is extremely relevant to recognize the importance of a good balance between static and dynamic occlusion and all related craniofacial structures represented by temporomandibular joint (TMJ) and the neuromuscular system for both oral rehabilitation and long-term stability. A final orthodontic result that respects these parameters is the best tool for physiological retention, with no need for external mechanical elements (Figure 8).
\n(a) Clinical check at 7 years of follow-up. (b) Clinical check at 13 years of follow-up. (c) Panoramic radiograph at 13 years of follow-up. (d) Periodontal radiographic status before the therapy and 13 years after the therapy with no fixed orthodontic retainer.
The authors acknowledge the financial support of EU-Marie-Curie-IAPP LUSTRE (324538) project.
\nCancer induced bone pain (CIBP) is a big accompanying clinical problem of bone tumors with a high unmet medical need [1]. It is a debilitating form of different pain components that severely affects a patients’ quality of life. The complex mechanism of CIBP largely involves the nervous system with transmembrane receptors and channels on the nerve fibers. Briefly, the nervous system consists of the central nervous system, i.e. the brain and the spinal cord, and the peripheral nervous system, i.e. the autonomic (unconscious, the para- and sympathetic nervous system) and somatic (conscious/voluntary) nervous system. A neuron is a nerve cell consisting of a cell body (soma), projections receiving input signals (the dendrites) and a single long arm away from the soma (the axon/fiber) that ends with the axon terminal (synapse). Axons contain a sheath of myelin that serves as isolation in a similar way as plastic around an electrical wire. Regarding the somatic nervous system, neurons with projections towards the spinal cord (afferent) respond to stimuli and are the sensory neurons. The neurons that respond to the brain and the signals from the spinal cord (efferent) are the motor neurons [2].
Pain is the defense mechanism against external factors that could cause tissue damage (a noxious stimuli) and nociception is detecting such stimulus. The somatosensory nervous system contains the sensory neurons that respond to noxious stimuli (nociceptors). There are three types of nociceptors, receptors that sense 1) thermal, 2) mechanical and 3) chemical stimulants. When a threshold of either one of those three properties is exceeded, the nociceptor is activated –
Pain can be acute, serving a biological purpose, e.g. protection, and chronic, without a biological purpose, becoming an own medical disease more than a symptom [3]. A workgroup from the international association for the study of pain (IASP) has defined chronic pain as a pain that persists for more than 3 months. They defined a subgroup in 2018 where it has been considered that pain can be the primary disease, i.e. in low-back pain. Moreover, they have made subgroups and considered conditions with chronic secondary pain, such as chronic cancer-related pain [4]. The transition to chronic pain involves neuronal plasticity –
This chapter elaborates on the mechanism of action of bone cancer pain. Next, a brief subsection of the bone anatomy & physiology. Finally, treatment options used for CIBP and bone metastases are described, including CIBP models to assess novel compounds and the mechanism of action.
Bones can be classified by their shapes, i.e. flat, short, long and irregular bones [7]. The most common bones that encounter metastasis of tumor cells are long bones [8, 9], i.e. the tibia, femur and humerus, characterized by an extended tubular diaphysis and round-shaped distal and proximal epiphyses [10]. The outer part is covered with a fibrous layer and an inner osteogenic layer, the periosteum and cambium layer, respectively [11]. The latter contains progenitor cells for the bone building cells, osteoblasts [11]. Briefly, mesenchymal-derived cells are the progenitors which are stimulated by the transcription factors core binding factor α1 (Cbfa1), Osterix (Osx) and activating transcription factor 4 (ATF4) to initiate osteoblastogenesis [12]. Matured osteoblasts secrete bone matrix until they become resting osteoblastic cells (bone-lining cells) [7, 12, 13]. Behind the periosteum are densely packed tube-like structures called osteons (Haversian system). One osteon consists of several layers (lamella) with small gaps (lacunae) in between, containing nutrient transportation cells, osteocytes, constituting 90 to 95% of the bone cells present in the mature human skeleton [7, 13]. Osteocytes originate from differentiated bone-linings cells after they are encapsulated by secreted bone matrix and are suggested to coordinate the location of bone formation or resorption [12]. The packed osteons is the bone matrix, surrounding and protecting the medullary cavity of the diaphysis, containing bone marrow, with a thin connective tissue membrane separating both. The hematopoietic lineage in the bone marrow is responsible for pre-osteoclastogenesis [14, 15]. The macrophage colony-stimulating factor (M-CSF) stimulates the progenitor bone marrow cell for differentiation into a pre-osteoclast, initiating the expression of the receptor activator of NF-κB (RANK) receptor [16, 17]. The osteoblasts express the opposite part of the RANK receptor, necessary for activation, the RANK ligand (RANKL). Upon activation of RANK by RANKL the osteoblasts ensure that several activated pre-osteoclasts fuse together, forming a larger multinucleated mature osteoclast [16]. A mature osteoclast is a specialized macrophage with multiple mitochondria and lysosomes, prepared for bone degradation [14, 15]. In addition, the cell–cell fusion process of pre-osteoclasts forming a mature osteoclast has a checkpoint, the stromal cells, which have the ability to interfere by secretion of Osteoprotegerin (OPG). This is a decoy receptor able to bind excessive levels of RANKL, preventing over-population of osteoclasts [9, 16, 18, 19]. Subsequently, the degradation of bone is initiated after maturation of osteoclasts and their allocation to the site-of-destruction, where they form a closed space, the resorption lacuna. Activation of H+-ATPase proton pump and Cl/HCO3 exchanger by osteoclasts follows, in combination with the secretion of lysosomal enzymes and active protease Cathepsin K into the lacuna [15]. The net effect of this cascade is an acidic environment of pH ± 4.5 to degrade the nearby bone cells [9, 15]. This triad of RANK/RANKL/OPG that regulates osteoclast activation is an important process in healthy bone physiology and plays an important role during bone cancer pain development [16, 17, 18, 19, 20]. Finally, At the level where the diaphysis reaches the proximal epiphysis, the medullary cavity is more spongy-like and is called trabecular or cancellous bone. Both epiphyses are composed primarily of spongy bone and a small quantity of compact bone, surrounded by cartilage [7].
Nociceptors are necessary to let the brain perceive CIBP, however, very little is known regarding the innervation of bone with sensory nerve fibers. Immunoreactivity studies have shown that sensory neurons are present in periosteum, cambium, bone matrix, Haversian canals and in bone marrow in the medullary cavity, and no detection was found in the articular cartilage of the epiphysis [21, 22, 23, 24, 25, 26, 27, 28, 29]. The density (nerves per unit area) of sensory fibers is largest in the periosteum, followed by bone marrow, mineralized bone and articular cartilage consisting in a ratio of 100:2:0.1:0, respectively [9, 10, 28]. Up to 80% of the nerve fibers innervating the bone have been shown TrkA positive [22], suggesting innervation of mostly thin myelinated Aδ-fibers and unmyelinated C-fibers [9, 10, 29, 30]. It seems that the fast conducting, highly myelinated Aβ-fibers do not contribute, or very scarcely, to the innervation of sensory neurons in the bone [29].
The world health organization (WHO) report from 2014 predicted that a total of 19 million cancer cases exist globally in 2025 [18] and in 2018 a WHO press release announced that lung (2.09 million cases), breast (2.09 million cases), colorectal (1.08 million cases) and prostate (1.28 million cases) are the most common [31]. All of these, except for colorectal, follow a high pattern of bone metastasis in 60 to 84% of the cases [9, 32]. In breast and prostate cancer patients particularly, it is expected that 90% develop bone metastases [33, 34]. Additionally, there are primary bone tumors that have their origin within the bone and the most common type is an osteosarcoma with a worldwide incidence of 3.4 cases per million people per year [35]. In pediatrics it accounts for 3 to 5% of the cancers and in adults less than 1% [8]. Tumors can affect osteoblasts, resulting in osteoblastic lesions and in contrast affect osteoclasts, causing osteolytic lesions [36]. Primary bone tumors, e.g. osteosarcoma, are more osteolytic [37], prostate cancer seems more osteoblastic and breast cancer osteolytic [38]. The latter two have been observed in 1/4th of the cases to be mixed [39]. A specific group of well-known signaling proteins, the Wnt pathway, is suggested to shift tumors towards an osteoblastic phenotype as blockage showed a highly osteolytic tumor [40]. This pathway has been observed to directly enhance osteoblast differentiation and bone formation, whereas indirectly inhibits osteoclast differentiation and bone resorption by OPG production from osteoblasts and osteocytes [41].
Some cancer patients encounter bone tumors without the presence of pain. Unfortunately, 30 to 50% of the patients will experience mild to moderate pain and in advanced cancer patients 75 to 90% have life-altering pain [37, 42]. The most prevalent type of pain experienced is bone cancer pain [9, 17, 33], which patients describe as a persistent presence of a dull ache that increases in intensity over time [32]. They start noticing mechanical allodynia during normal activities, such as coughing, turning in bed or gentle limb movements [43]. Furthermore, there is incident pain, that occurs when the pain spontaneously intensifies as a result of weight-bearing or during movement. Finally, there are breakthrough events of very sharp intense pain that can happen during rest [9, 32]. These breakthrough pain episodes occur in 40 to 80% of the patients with a median of 4 episodes per day, lasting up to 30 minutes [44]. Particularly the incident and breakthrough pain events are devastating for the quality of life and are considered as most difficult pain conditions to treat [9, 33].
The Aδ-fibers are recognized to be important in acute pain, whereas C-fibers are the slower conducting sensors that account for physiological changes such as “second pain” [9]. It has been observed during chronic pain that these start sprouting and show enhanced spontaneous activity, ectopic firing, resulting in allodynia and hyperalgesia [45, 46, 47, 48]. Important surface channels and receptors of Aδ- and C-fibers involved in nociceptive signaling are TrkA, acid sensing ion channels (ASIC), Transient receptor vanilloid-1 (TRPV1), P2X receptors, endothelin receptor (ET-1), bradykinin receptor (B2R), prostaglandin (PGE2) receptor, the voltage-gated sodium channels Na.v1.7–1.9 and cytokine receptors [9, 18, 29, 49].
The mechanism of CIBP in osteoblastic lesions is poorly understood and the most influential factors described are bone morphogenetic factors and endothelin-1. The mechanisms in osteolytic lesions have been better elucidated [36]. First, the infiltrating tumor cells start an interaction with the stromal cells, resulting in a cascade of different pathways, shown in Figure 1. A primary effect on sensory nerve fibers occurs as the secreted mediators, e.g. NGF, PGE2, transforming growth factor-β (TGF-β), bradykinin, endothelin, cytokines (e.g. IL-1, IL-6, IL-8, IL-11 and IL-17) are ligands for the receptors and cause excitation of the nerve fibers [17, 22, 29, 50, 51, 52, 53]. It has been shown in a rat CIBP model that IL-6 plays a pivotal role by sensitizing nociceptive fibers, mediating peripheral and spinal sensitization [54] by upregulation of TRPV1 receptors via JAK/PI3K signaling in dorsal root ganglia neurons [55]. In addition, PGE2, TGF-β, IL-1, IL-6, IL-8, IL-11 and IL-17 showed to be involved in a secondary effect, namely the ability to increase the expression of RANKL and decrease OPG [17, 19, 52, 56]. TGF-β is also released by the bone matrix and stimulates osteolytic bone destruction of cells close to the tumor cells [56]. The normally present OPG that serves as a peace-keeper between osteoclasts and osteoblasts is overwhelmed by the excessive amounts of RANKL, resulting in exaggerated activity of osteoclasts [19]. Consequently, osteoclastogenesis is initiated resulting in many resorption lacunae creating an acidic environment [20]. Additional pro-inflammatory cells become active, secreted cytokines bind their designated receptors and proton (H+ & Na+) amounts increase, lowering the pH and thereby triggering P2X7 and TRPV1 receptors, and ASICs [1, 20, 49]. The rapid Na+ influx is associated with ASICs and a second slow current activated at pH < 6.2 is typical for TRPV1 [20]. Subsequently, tumor cells release NGF, tumor necrosis factor (TNF), IL-1 and IL-6, chemokines and endothelins which contribute to further develop an acidic environment [32]. This could be the explanation regarding the difficulty of treating CIBP [29].
The cascade of events responsible after infiltration of a tumor cell, resulting in CIBP with a nociceptive and neuropathic component. First, disturbance of the RANK/RANKL/OPG triad. Next, the nociceptive component; an acidic environment occurs, directly activating sensory nerve fibers and secreted mediators contribute to the upregulation of RANKL. In addition, the neuro-inflammatory mediator upregulates TRPV1 channels. The neuropathic component; nerves are damaged and denervate, resulting in ectopic firing and sprouting and an enlarged tumor activates mechano-sensitive nociceptors. The NGF/TrkA is pivotal in the process of sprouting and thereby for hypersensitivity. RANK = receptor activator of NF-κB, RANKL = RANK ligand, OPG = osteoprotegerin, Na.v1.7–1.9 = sodium channels, P2X = purinergic receptor, TrkA = Tromomyocin receptor kinase a, NGF = nerve growth factor, ET1 = endothelin receptor, B2R = bradykinin receptor, ATP = Adenosinetriphosphate, IL-6 = interleukin-6, ASIC = acid-sensing ion channel, TRPV1 = transient receptor vanilloid-1, TGF-β = transforming growth factor-β, TNF = tumor growth factor.
Next to the nociceptive component of CIBP is the neuropathic component, caused by damage or denervation of nerves, pressure of tumors on the nerves and sprouting. The degradation of bone and the damage that occurs can activate mechanosensitive ion channels, e.g. TRPV, ASIC and P2X7 [29, 57, 58]. Activated NGF regulates the maintenance of the peripheral sensory neuron system and initiates sprouting of adjacent non-injured afferents upon injury or denervation, resulting in collateral sprouting [59, 60]. Random sprouting of sensory neurons co-expressing TrkA was shown in prostate cancer metastases [9, 48] and similar in breast cancer metastases [47]. Hypersensitivity occurs as a result of sprouting, causing sensitization of sensory nerves, which in its turn induces mechanonociception (by Aδ-fibers) [59]. Changes also have been shown to occur in the central nervous system in the spinal cord where the excitatory synaptic transmission mediated through A-δ and C-fibers was enhanced [61].
On the one hand, it is suggested that the increase in activated osteoclasts causes the development of CIBP while on the other hand the secreted mediators directly exciting sensory nerve fibers is suggested to be the primary explanation [17, 51]. Nevertheless, all these multidisciplinary factors –
When a patient experiences bone cancer pain, the first step of therapy is tumor eradication, i.e. via chemotherapy and radiation, unfortunately in <50% of the patients the pain levels will return to pre-treatment levels [62]. Radiotherapy, described as the golden standard palliative therapy, shows full pain relief in 25% of treated patients, however, only after a month [29]. Different radiotherapy protocols showed a single radiotherapy fraction (8Gy) provides equal pain palliation compared to multiple fractions (30 or 20 Gy in 10 or 5 fractions, respectively) [63]. Low fractionated radiotherapy also caused a higher incidence of pathological fractions at site of irradiation [1]. Chemotherapy is an option for the treatment of CIBP when the tumor histology is more nociceptive, the patient did not previously receive chemotherapy and when the tumor is chemosensitive [64]. However, oxaliplatin and paclitaxel are used for animal models of induced-neuropathy to investigate hypersensitivity [65, 66].
Bisphosphonates are agents that are often used to treat pain as a symptom [67]. They act by inhibiting farnesyl diphosphate synthase in phagocytic cells, e.g. osteoclasts, macrophages and microglia, thereby decrease extracellular acidification and consequently reduce ASIC- and TRPV1-mediated activation of nociceptive primary afferents located in bone [67]. Other effects of bisphosphonates unrelated to farnesyl diphosphate synthase inhibition that have been suggested are interactions with purinergic receptors, e.g. P2X7. The bisphosphonate zoledronate exerted an analgesic effects in rat CIBP models [68]. It is the most widely used bisphosphonate, also observed to significantly reduce CIBP in clinical practice for breast cancer metastases [69], being 100 to 1000 times more effective than pamidronate [70]. Furthermore, anti-inflammatory effects have been indicated where alendronate inhibited TNF-α, IL-1, IL-6 and NGF [67].
Monoclonal antibody therapies have the ability to interfere with tumor-induced processes, e.g. RANK/RANKL, NGF/TrkA, and inhibit or avoid cytotoxic T lymphocyte [71]. A hand full of these therapies have been FDA approved for cancer therapy and a small amount has been tested in breast, prostate or lung cancer metastases [71]. Tanezumab is a monoclonal antibody interfering with NGF/TrkA and has been described unbeneficial in one CIBP study [72], however, has also been shown to attenuate late stage cancer pain [73]. Denosumab is another monoclonal antibody and acts by interfering with the interaction between RANK/RANKL, capturing RANKL, resulting in osteoclast inactivation [74]. Denosumab has been tested as treatment in breast cancer metastases and while it showed a good activity profile for delaying or preventing skeletal related events, no direct relief of pain has been described. Nevertheless, the delay and/or prevention of skeletal related events would have an indirect pain-impairing potential as such events are associated with pain and increased morbidity [75]. Denosumab did show superiority concerning first on-study skeletal-related events compared to zoledronate [76]. Similar outcomes were found by a meta-analysis of 4 RCTs between denosumab and zoledronate [77]. Regarding the dosing, a study showed no difference between 4-weekly and 12-weekly administration for denosumab and the two bisphosphonates zoledronate and pamidronate, suggesting that incorporating 12-weekly dosing could benefit patients [78]. Denosumab seems to be the only antibody therapy so far that is approved for direct treatment of skeletal-related events with bone metastases from solid tumors and giant cell tumors of the bone [71]. Ipilimumab is an antibody that activates the immune system, specifically, inhibits an inhibitory mechanism of cytotoxic T lymphocytes. It was tested in metastatic prostate cancer in combination with radiotherapy and suggested clinical antitumor activity [79]. Nivolumab therapy was recently tested in lung cancer metastases into the bone and showed that 40% of the treated patients had osteosclerotic change on CT scans, indicating successful treatment of bone lesions [80]. The small amount of monoclonal antibodies used for bone metastases often have skeletal related events as indication of efficacy but lack bone cancer pain as direct outcome measure. Currently there are no recorded monoclonal antibodies specifically targeting CIBP.
Available options for the direct treatment of CIBP are analgesics. The WHO has established a 3-step ladder as a guideline for analgesic prescription in 1986 and revised the version in 1996 with a quick guide to opioid availability [81]. Afterwards, the stigma on opioid prescription was broken and received acceptance as treatment for (chronic) pain conditions [82, 83, 84]. The 3-step ladder starts with non-opioids (Step 1) for mild pain, weak opioids ± non-opioids and adjuvants for mild to moderate pain (Step 2), and strong opioids ± non-opioids and adjuvants for moderate to severe pain (Step 3) [85].
First in line are NSAIDs that inhibit the enzyme cyclooxygenase-2 (COX-2), responsible for PGE synthesis [64]. A challenge with NSAIDs is that they reach a ceiling effect in analgesic efficacy [81, 86]. Increasing the doses does not result in increased efficacy, conversely, side effects worsen, further impairing the quality of life of patients [86, 87]. Second in line are weak opioids, e.g. codeine, tapentadol or tramadol, in combination with adjuvants, indicating proven analgesic efficacy in bone cancer pain [88]. There are three classical opioid receptors, e.g. the μ-, δ- and κ-opioid receptors (MOP, DOP and KOP receptor, respectively) and the later discovered Nocicpetin/OrphaninFQ opioid peptide (NOP) receptor [89]. These receptors are G-protein coupled receptors and upon activation initiate an intracellular cascade resulting in 1) the inhibition of adenylate cyclase (responsible for cAMP production), 2) opening of inwardly rectifying K+ channels and 3) closing of voltage-gated Ca2+ channels [89]. Caution must be exercised with weak opioids as the rate of metabolism by Cytochrome P450 enzymes defines analgesic efficacy and side effects. In addition, codeine seemed effective for only 1 month until strong opioids were necessary for adequate analgesia [90, 91]. A randomized RCT trial showed significant impairment of cancer pain by low-dose morphine compared with weak opioids, with similar tolerability and an earlier effect, suggesting low-dose morphine can be used [90, 92]. This forwards the therapy option towards Step 3 and to date, the first choice to treat moderate to severe pain with strong opioids remains morphine [90, 93]. MOP receptor drugs have shown superior analgesic efficacy and have been used for centuries as they seem to be the most potent analgesics [94]. Available options for administration are oral and transdermal, showing similar efficacy, and advocated is the use of epidural or intrathecal pumps if relief is inadequate [90]. Concerning side effects of MOP receptor drugs are addiction and dependency. The opioid crisis is prove and accounted for 33.000 deaths per year in the US by opioid misuse [94, 95, 96]. In addition, cancer survivors showed higher opioid prescription compared to controls [97]. The total estimated economic burden due to opioid addiction, dependency, abuse and overdose is $78.5 billion, from which $28.9 billion is due to increased health care and abuse treatment [98]. Furthermore, analgesic efficacy of MOP receptor compounds is affected by long term opioid treatment as tolerance develops over time [99, 100]. This is inevitable in cancer patients since high doses are required for pain management [101]. The mechanism that contributes pre-synaptically to tolerance remains to be elucidated but TRPV1 receptor upregulation in spinal cord and dorsal root ganglions has been shown to accompany tolerance [99, 100].
Challenging is to find analgesics with a similar potency and efficacy compared to MOP receptors, without dependency and addiction. Targeting the DOP and KOP receptor showed efficacious pain relief with a lower abuse potential, making them promising targets for treating pain [102]. Specifically for CIBP, both DOP and KOP receptor agonists showed pain attenuation in animal models of CIBP [103, 104]. It has been shown that a selective KOP receptor agonist blocked pain without altering bone loss, tumor size or cancer cell proliferation [105]. Additionally, a DOP receptor agonist showed equal analgesic efficacy and 4.5-fold potency compared to morphine in a mouse CIBP model [106]. Despite potential analgesic efficacy, MOP receptor agonists remain the clinical mainstay [107, 108]. Interest in the NOP receptor increased after the discovery of similar, yet distinct features compared to the classical opioids [109]. The effects of classical opioids are immediately blocked by naloxone and independently of administration location, they attenuate pain. The analgesic NOP receptor effect remains after naloxone and interestingly, spinal or peripheral activation exerts anti-nociceptive effects, while supra-spinally it acts pro-nociceptive [85, 109]. Following these discoveries, the NOP receptor showed anti-rewarding and anti-abuse effects in rodents [85, 110, 111, 112, 113]. Furthermore, NOP receptor expressing Chinese Hamster Ovary cells showed rapid internalization after activation and a quick recycle process to reactivate receptors occurred at the membrane, potentially reducing the development of tolerance. However, compensatory mechanisms that remain to be elucidated may be overlooked [114]. The NOP receptor has been specifically used to target CIBP and both the endogenous ligand Nociceptin and a synthetic selective NOP receptor agonist (Ro65–6570) showed significant analgesia [85]. Furthermore, NOP receptor activation downregulates IL-6 production [115] and is suggested to inhibit T cell proliferation [116]. Altogether, the anti-rewarding and anti-abuse effects, cytokine production involvement and selective attenuation of CIBP, makes the NOP receptor an interesting target.
Differences should be kept in mind when treating tumors, nevertheless, anti-NGF antibody therapy has been observed to relief early and late stage CIBP in a primary bone tumor model and a metastatic-like prostate bone cancer model [37]. In addition, zoledronate has been shown effective in reducing the risk of skeletal related events in multiple myeloma, prostate and breast cancer bone metastasis [117]. Denosumab indicated superiority to zoledronate in preventing skeletal related events in bone metastasis compared to solid tumors, suggesting a treatment option for bone metastasis [118]. Primary bone tumors are characterized by high complexity and heterogeneity in genomic alterations and are therefore challenging for developing targeted therapeutic strategies [41] which also may not satisfactorily address their metastatic counterparts [119].
The WHO analgesic ladder has proven to be very helpful, nevertheless, an estimated 12% of patients remains inadequately treated for CIBP [120]. Therefore, a fourth step has been proposed that includes interventional approaches to provide a minimal acceptable quality of life [120, 121, 122]. As such, percutaneous neurolysis is performed using chemical agents or thermal energy upon celiac plexus, splanchnic nerve, superior hypogastric plexus, brachial plexus and epidural and intrathecal [120, 122]. Commonly used neurolytic agents are absolute alcohol (diluted to 50% alcohol), 6% aqueous phenol and 6% phenol in glycerine [120].
Finally, PET/CT allows the distinction between osteolytic and osteoblastic lesions and thereby detect more subtle responses to treatment regimens [123]. Using CT in the surgical planning could shift the priority of debulking dense bone to surgical reconstruction when bone metastasis is more osteolytic instead of osteoblastic [39].
The current treatments are often targeted against pain as a symptom and therapy options specifically for CIBP are rare. To elucidate the complex mechanism of action of CIBP and develop novel analgesics, further research is warranted. As such,
At start, to reflect metastases as closely as possible, cancer cells were injected either intravenously or intra-cardially. Face validity is achieved but uncontrolled growth of tumors occurs [32, 126, 127]. Next came the technique of injecting osteosarcoma-derived mesenchymal cells (NCTC-2472) directly into the long bones of mice [128]. This technique indicates good face and predictive validity, resulting in a controlled late-phase CIBP model, reflecting the clinical course with a comparable responsiveness to systemic opioid treatment [32, 128]. Finally, construct validity had been optimized using syngeneic cell lines (originating from the same species). The first example was rat mammary gland carcinoma cells (MRMT-1 cell line) inoculation into the tibia of rats [129]. The main characteristics after inoculation of cancer cells are: development of allodynia and hyperalgesia, progressive tumor growth, profound destruction and rebuilding of bone and no external tumor growth into other organs. In addition, upregulation of TNF-α, Interferon- γ (IFN-γ), IL-1β, IL-4, IL-10 and IL-6 occurs in tumor-bearing animals [49, 130]. Fine-tuning occurred with another rat breast cancer cell line (Walker 256 cells) inoculated into the tibia [131]. This model has been reviewed extensively and develops spontaneous pain, hyperalgesia, allodynia as well as ambulatory pain, indicates progressive tumor growth with osteolysis and no external growth, including upregulation of IL-1β, NGF, PGE2, IL-6 and TNFα [132]. This model has been subjected to a detailed pharmacological profiling using standard analgesic drugs for CIBP in a clinical setting and is suggested to be one of the most suitable preclinical models for novel compound identification and assessment [132, 133]. No study has been conducted comparing the Walker 256 model with the MRMT-1 model (Figure 2).
A representation of the different in vivo models to study cancer induced bone pain.
Cancer-induced bone pain (CIBP) causes life-altering pain in 75 to 90% of the advanced stage cancer patients. The movement-induced incident and breakthrough events cause a severe impairment of the quality of life of patients and explain the difficulty to treat this unique type of pain. There remains a high unmet medical need for CIBP treatment since around one-third of the advanced cancer patients is still undertreated [90]. Apparent from the mechanism of actions is that CIBP concerns distinct processes and could be treated by pharmacological and non-pharmacological options. Strategies are to combine therapies, such as co-administration of zoledronate via a new innovative nano-agent with cisplatin and alendronate for breast cancer metastases and bone resorption, showing remarkable inhibition of tumor cell proliferation, osteoclast activation and bone pain relief [134]. Mixed ligands are another strategy, such as Cebranopadol, a mixed NOP/Opioid receptor ligand, indicating antinociceptive and antihypersensitive effects in a rat model of CIBP [135]. A meta-analysis comparing the efficacy of NSAID, opioids and monoclonal NGF antibodies indicate the latter provide superior pain relief, noteworthy is that this was in osteoarthritis [136]. As new strategies are arising, bisphosphonates and denosumab are the first-line therapies for bone metastases [38] and continuing research is warranted to elucidate the CIBP mechanism for identifying novel analgesic compounds.
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\\n\\nIf a manuscript is submitted by an Author who is a member of an Academic Editor's family or is personally or professionally related to the Academic Editor in any way, either as a friend, colleague, student or mentor, the work will be handled by a different Academic Editor who is not in any way connected to the Author.
\\n\\nCONFLICT OF INTEREST - REVIEWER
\\n\\nAll Reviewers are required to declare possible Conflicts of Interest at the beginning of the evaluation process. If a Reviewer feels he or she might have any material, financial or any other conflict of interest with regards to the manuscript being reviewed, he or she is required to declare such concern and, if necessary, request exclusion from any further involvement in the evaluation process. A Reviewer's potential Conflicts of Interest are declared in the review report and presented to the Academic Editor, who then assesses whether or not the declared potential or actual Conflicts of Interest had, or could be perceived to have had, any significant impact on the review itself.
\\n\\nEXAMPLES OF CONFLICTS OF INTEREST:
\\n\\nFINANCIAL AND MATERIAL
\\n\\nNON-FINANCIAL
\\n\\nAuthors are required to declare all potentially relevant non-financial, financial and material Conflicts of Interest that may have had an influence on their scientific work.
\\n\\nAcademic Editors and Reviewers are required to declare any non-financial, financial and material Conflicts of Interest that could influence their fair and balanced evaluation of manuscripts. If such conflict exists with regards to a submitted manuscript, Academic Editors and Reviewers should exclude themselves from handling it.
\\n\\nAll Authors, Academic Editors, and Reviewers are required to declare all possible financial and material Conflicts of Interest in the last five years, although it is advisable to declare less recent Conflicts of Interest as well.
\\n\\nEXAMPLES:
\\n\\nAuthors should declare if they were or they still are Academic Editors of the publications in which they wish to publish their work.
\\n\\nAuthors should declare if they are board members of an organization that could benefit financially or materially from the publication of their work.
\\n\\nAcademic Editors should declare if they were coauthors or they have worked on the research project with the Author who has submitted a manuscript.
\\n\\nAcademic Editors should declare if the Author of a submitted manuscript is affiliated with the same department, faculty, institute, or company as they are.
\\n\\nPolicy last updated: 2016-06-09
\\n"}]'},components:[{type:"htmlEditorComponent",content:"In each instance of a possible Conflict of Interest, IntechOpen aims to disclose the situation in as transparent a way as possible in order to allow readers to judge whether a particular potential Conflict of Interest has influenced the Work of any individual Author, Editor, or Reviewer. IntechOpen takes all possible Conflicts of Interest into account during the review process and ensures maximum transparency in implementing its policies.
\n\nA Conflict of Interest is a situation in which a person's professional judgment may be influenced by a range of factors, including financial gain, material interest, or some other personal or professional interest. For IntechOpen as a publisher, it is essential that all possible Conflicts of Interest are avoided. Each contributor, whether an Author, Editor, or Reviewer, who suspects they may have a Conflict of Interest, is obliged to declare that concern in order to make the publisher and the readership aware of any potential influence on the work being undertaken.
\n\nA Conflict of Interest can be identified at different phases of the publishing process.
\n\nIntechOpen requires:
\n\nCONFLICT OF INTEREST - AUTHOR
\n\nAll Authors are obliged to declare every existing or potential Conflict of Interest, including financial or personal factors, as well as any relationship which could influence their scientific work. Authors must declare Conflicts of Interest at the time of manuscript submission, although they may exceptionally do so at any point during manuscript review. For jointly prepared manuscripts, the corresponding Author is obliged to declare potential Conflicts of Interest of any other Authors who have contributed to the manuscript.
\n\nCONFLICT OF INTEREST – ACADEMIC EDITOR
\n\nEditors can also have Conflicts of Interest. Editors are expected to maintain the highest standards of conduct, which are outlined in our Best Practice Guidelines (templates for Best Practice Guidelines). Among other obligations, it is essential that Editors make transparent declarations of any possible Conflicts of Interest that they might have.
\n\nAvoidance Measures for Academic Editors of Conflicts of Interest:
\n\nFor manuscripts submitted by the Academic Editor (or a scientific advisor), an appropriate person will be appointed to handle and evaluate the manuscript. The appointed handling Editor's identity will not be disclosed to the Author in order to maintain impartiality and anonymity of the review.
\n\nIf a manuscript is submitted by an Author who is a member of an Academic Editor's family or is personally or professionally related to the Academic Editor in any way, either as a friend, colleague, student or mentor, the work will be handled by a different Academic Editor who is not in any way connected to the Author.
\n\nCONFLICT OF INTEREST - REVIEWER
\n\nAll Reviewers are required to declare possible Conflicts of Interest at the beginning of the evaluation process. If a Reviewer feels he or she might have any material, financial or any other conflict of interest with regards to the manuscript being reviewed, he or she is required to declare such concern and, if necessary, request exclusion from any further involvement in the evaluation process. A Reviewer's potential Conflicts of Interest are declared in the review report and presented to the Academic Editor, who then assesses whether or not the declared potential or actual Conflicts of Interest had, or could be perceived to have had, any significant impact on the review itself.
\n\nEXAMPLES OF CONFLICTS OF INTEREST:
\n\nFINANCIAL AND MATERIAL
\n\nNON-FINANCIAL
\n\nAuthors are required to declare all potentially relevant non-financial, financial and material Conflicts of Interest that may have had an influence on their scientific work.
\n\nAcademic Editors and Reviewers are required to declare any non-financial, financial and material Conflicts of Interest that could influence their fair and balanced evaluation of manuscripts. If such conflict exists with regards to a submitted manuscript, Academic Editors and Reviewers should exclude themselves from handling it.
\n\nAll Authors, Academic Editors, and Reviewers are required to declare all possible financial and material Conflicts of Interest in the last five years, although it is advisable to declare less recent Conflicts of Interest as well.
\n\nEXAMPLES:
\n\nAuthors should declare if they were or they still are Academic Editors of the publications in which they wish to publish their work.
\n\nAuthors should declare if they are board members of an organization that could benefit financially or materially from the publication of their work.
\n\nAcademic Editors should declare if they were coauthors or they have worked on the research project with the Author who has submitted a manuscript.
\n\nAcademic Editors should declare if the Author of a submitted manuscript is affiliated with the same department, faculty, institute, or company as they are.
\n\nPolicy last updated: 2016-06-09
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