Indications for Dental Specialists for Treating Obstructive Sleep Apnea with Mandibular Advancement Devices: A Narrative Review

Obstructive sleep apnea (OSA) syndrome is characterized by repeated airway collapse during sleep. It determines cardiovascular, pulmonary, and neurocognitive consequences and is associated with several daytime and nighttime symptoms that influence the patient's quality of life. The contribution of the dental specialist in the clinical management of OSA patients entails participating in the screening process as diagnostic sentinels and providing adequate treatment using mandibular advancement devices (MADs). Since the treatment of OSA requires a multidisciplinary approach, including different medical specialists, dentists should have a comprehensive understanding of medical and dental factors that influence the strategy and effectiveness of OSA treatment with MAD. Such expertise is crucial in determining the appropriate treatment indications and helps clinicians establish a consolidated position within the multidisciplinary OSA team. In this regard, this review summarizes the evidence of the clinical indications for MAD treatment and provides the dental specialist with helpful information about medical, functional, and other relevant factors that should be considered during diagnosis, treatment plan, and follow-up stages. Information retrieved was organized and discussed, generating specific domains/queries oriented to the clinical management of OSA patients from the clinical perspective of dental specialists.


Introduction
Obstructive sleep apnea (OSA) is a sleep-breathing disease affecting the adult population between 9% and 38% [1,2].OSA is defined as the occurrence of five or more episodes of upper airway obstruction, complete (apnea) or partial (hypopnea), per hour during sleep, caused by collapsibility of the upper airway [3,4].The polysomnographic examination is the gold-standard diagnostic tool for analyzing respiratory disturbance, distinguishing obstructive apnea or hypopnea episodes primarily from those of central origin [5,6].The polysomnographic parameters used to perform diagnosis and define the severity of OSA are the apnea-hypopnea index (AHI) and the respiratory disturbance index (RDI), the latter including the number of respiratory effort-related arousals per hour of sleep in addition to apnea and hypopnea events [7,8].OSA is scored as mild (>5 events/hr AHI/RDI), moderate (>15 events/hr AHI/RDI), and severe (>30 events/hr AHI/RDI).OSA is associated with metabolic and cardiovascular dysfunction [9,10], and it is considered to be a systemic life-threatening disease as patients with untreated sleep apnea have an increased risk of mortality [11,12].
Continue positive airway pressure (CPAP) is the most effective treatment for patients with OSA [7,13].Despite its proven effectiveness, patients often report low adherence to the treatment [7,[14][15][16][17].For this reason, new therapies and strategies have been advocated and explored in clinical and research settings [18].The International and European guidelines [5,19] clearly reported that the clinical management of OSA patients must involve a multidisciplinary group of experts, including pulmonologists, neurologists, otolaryngologists, dental specialists, surgeons, and nutritionists.
The role of the dental specialist entails participating in the screening process as diagnostic sentinels and during the treatment phase when the use of mandibular advancement devices (MADs) is advocated.In this context, extensive scientific evidence has confirmed that MADs serve as a first-line treatment approach for individuals with mild OSA as well as for adults diagnosed with moderate to severe OSA who do not respond or tolerate the CPAP [20,21].Systematic reviews have also focused on the efficacy of MAD therapy in relation to single specific aspects such as device design [22][23][24], predictive factors [25], side effects [26,27], and treatment adherence [28].This indicates that dental specialists play an active role in the followup and long-term monitoring of the patient's respiratory performance, particularly when MAD treatment is conducted in conjunction with other therapies.It also implies that dental specialists should acquire expertise in the management of OSA patients, encompassing a comprehensive understanding of medical and dental factors that influence the strategy and effectiveness of OSA treatment with MAD.Such expertise is crucial in determining the appropriate treatment indications and establishing a consolidated position within the multidisciplinary OSA team.However, the existing literature is lacking of a broad overview addressing the actual evidence-based medical and dental indications for MAD treatment and which factors the dental specialists should consider for the treatment of OSA patients; this information, collected together, would facilitate dental specialists in interacting with the other specialists of the OSA multidisciplinary team.In this regard, the present review aims to provide a summary of evidence of the clinical indications for MAD treatment and to provide the dental specialist with useful information about medical, functional, and orodental relevant factors that should be considered during diagnosis, treatment plan, and follow-up stages.

Materials and Methods
Database searches were performed until July 2023 to evaluate the published literature on the topic.A plentiful search strategy was applied for each database using combinations with "generic" terms (i.e., "osa" AND "mad mandibular advancement device"), and the selected databases were PubMed (https://pubmed.ncbi.nlm.nih.gov) and Scopus (https://www.scopus.com/search/form.uri?display=basic#basic).Clinical longitudinal studies dealing with adult subjects affected by OSA and in treatment with MAD as exclusive treatment or in combination with other therapies were included.The reference list of all included sources of evidence was screened for additional studies.Two authors (A.L.G. and S.L.R.) evaluated titles and abstracts retrieved from the databases, and any disagreement will be resolved after consulting another author (R.L.).No restrictions regarding the year or language of publication were applied.

Results and Discussion
After duplicate removal, 2,670 records were screened by the reviewers, and a total of 209 studies were considered for final inclusion.The review included 61 clinical studies, while 30 were systematic reviews and 7 were reviews.Table 1 presents the main characteristics of the studies included for final inclusion in the manuscript.To better address clinical indications and, considering the different types of information retrieved and the significant number of studies included, results were organized and discussed, generating specific domains/queries that covered all the information retrieved in the included studies.A schematic simplified overview of the information reported in the present review is illustrated via flow-diagram in Figures 1 and 2.

Factors, Not Assessable by the Dental Specialist, Predicting
the Effectiveness of MAD Therapy 3.1.1.Age.Younger adults have greater responsiveness to the MAD treatment compared to older subjects [29,30].In this regard, aging could negatively influence the effectiveness of the treatment due to the deterioration of the structure and function of the superior airway.With aging, the hypoxic response during sleep decreases, the breathing muscles have less tensile strength and fatigue resistance [31,32], the ventilatory system during sleep is more unstable [33], the strength of the upper airway dilatator muscle reduces, and the pharyngeal closing pressure and upper airway resistance and laxity increase [34].One study [34] found a progressive long-term (10 years) reduction of the efficacy of the treatment after the initial reduction of AHI values at 1 year and 2 years follow-up.
Although the AHI values recorded at 10 years were within the clinically acceptable range of treatment success (>50% AHI reduction), this finding would encourage the necessity to monitor treatment progress, changes in lifestyle, and health status in the long term to evaluate the integration or the substitution with CPAP device.Furthermore, compliance with MAD treatment seems to decrease with time, particularly from the 6th decade, when the patient's ability or willingness to adapt to an intraoral appliance was associated with an increased number of dropouts [35,36].As a consequence, the efficacy of MAD could be influenced by patients' age and dentists should dedicate time (clinical appointments) and appropriate tools (including questionnaires) for motivating older subjects to the treatment at the baseline.However, treatment motivation should not be a major concern for those subjects who have experienced CPAP since studies are almost unanimous in confirming that these patients show good adherence to the treatment with MAD.16 International Journal of Dentistry [37].The assumption is that the upper airway generates less resistance in females due to a smaller upper airway volume; also, female hormones may exert a protective effect on sleepdisordered breathing syndromes, which would reduce after menopause [38].In this regard, two studies [29,30] did not find an association between gender and treatment response, while one study [39] found that gender was a favorable predictive factor.However, since these studies did not discuss or argue such findings in detail, future studies guaranteeing the same treatment conditions between males and females are warmly encouraged to evaluate if gender may be considered a predictive factor for MAD treatment.International Journal of Dentistry 3.1.3.Body Weight.Positive responsiveness to MAD treatment was reported in association with lower baseline values of body mass index (BMI) and neck circumference [40,41].Obese subjects feature an enlargement of upper airway adipose tissue, which reduces the capability of opening the retropalatal airway space during MAD wearing [42][43][44].However, good responders were also found among subjects with higher BMIs and outside the currently recommended limits for clinical characteristics; thus, physiological characteristics alone should not be considered predictors of treatment responsiveness [25].However, from the clinical perspective, a strict diet regimen represents part of the treatment, and cooperation with the nutritionist is essential to monitor treatment progress.
3.1.4.Diagnostic Instrumental Parameters.Although the last European Respiratory Society guideline orientates clinicians to the usage of MAD as an alternative to CPAP in patients with mild to moderate OSA, the authors of the present review did not find agreement in the included studies in discriminating responders and nonresponders according to the AHI (or RDI) values.In this regard, lower baseline AHI values were positively associated with the responsiveness to the MAD treatment in some studies [45][46][47][48].In contrast, other studies [29,30,49] did not find differences according to the severity of the AHI.However, the night-to-night variability of AHI, the different criteria used to define responsiveness and the usage of different cutoff values could be the reasons ascribable to these uncertain findings.Thus, as far as the actual evidence is concerned, AHI and RDI alone should not represent reliable parameters in predicting the treatment success with MAD, but they could be considered along with other clinical characteristics [25,39].Several studies reported that MAD appliances effectively reduce the AHI recorded in the supine position.Also, in three studies, MADs were considered equal to protective positional therapy in managing patients affected by positional obstructive sleep apnea (POSA) [50][51][52].In this regard, the sleeping posture during PSG is an important element to discriminate the positional component within the overall AHI values [31,53,54], and supine-dependent sleep apneas could be a better predictor of treatment success than the disease severity measured by the total AHI [55,56].The positive impact of MAD appliances in reducing supine-AHI could be explained considering that the mandibular advancement mechanism is more effective in preventing the anteroposterior collapse, which, in POSA subjects, reflects a normal pharyngeal morphology with a normal airway in the lateral dimension [57,58].Instead, patients with apneas in the lateral position reflect a narrow airway in the lateral dimension, and problems in maintaining airway patency in the lateral sleeping position indicate a high risk of apneas [59].
3.1.5.Anatomical Factors.Anatomical characteristics represent a critical etiological factor in developing OSA, considering that the reduced dimension of the bony structures and the increased expansion of the soft tissue components augment the soft tissue pressure on the airway, increasing the airway collapsibility [48,60,61].
Since MADs maintain airway patency by displacing the mandible and attached soft tissues forward, the assumption is that the site of collapse during sleep is an important parameter to predict the responsiveness of the treatment [62].In this regard, primary oropharyngeal collapse, both at the level of the soft palate and tongue base, was associated with positive treatment response and should be considered a predictor of MAD response [29,39,63].Also, using druginduced sleep endoscopy (DISE) [64,65], a positive phenotype was associated with the collapse of the tongue base, while negative phenotypes included subjects with complete concentric collapse at the level of the palate and complete laterolateral oropharyngeal collapse.This finding would also explain the positive responsiveness to the MAD treatment in POSA subjects where the anteroposterior collapse pattern plays a positive predictive role compared to the later-lateral or concentric collapse pattern.
3.1.6.Cephalometric Parameters.Cephalometric analysis could represent another important tool to evaluate the predictability of the treatment with MAD at the baseline.Subjects affected by obstructive sleep apnea syndrome (OSAS) can feature an increased distance between the hyoid bone, which reduces with the usage of MAD [48,66].This explains the appliance's favorable biomechanics since positioning the mandible forward pulls the muscles attached to the hyoid bone, reducing the descent of the hyoid and increasing the pharyngeal airway patency.Mandibular retrognathia was found to be a common cephalometric data associated with good responders [67,68].One study reported that the responsiveness to the MAD treatment is not associated with skeletal parameters but rather with a larger tongue volume for a given oral cavity size, suggesting that MAD helps to correct anatomic imbalance [69].
In conclusion, the positive prediction of treatment with MAD relies not on identifying a single factor but rather on identifying a clinical phenotype featuring multiple integrated characteristics.Younger in age, lower BMI and neck circumference, the tendency to lower AHI values with the prevalent positional component, and primary oropharyngeal closure with anteroposterior collapse are baseline characteristics that would delineate a good responder phenotype.Urgent randomized clinical trials are needed to assess the predictability of both clinical, anatomical, hormonal, and instrumental parameters for the responsiveness to the treatment with MAD and to generate a predictive model or phenotype, identifying which variable is the most effective in this term.Since different treatments exhibit different mechanisms of action and the collapse of the upper airway occurs at multiple levels in most subjects with OSA [70,71], combined treatments could improve the overall therapeutic effectiveness.In this regard, MAD may be successfully combined with CPAP and nasal expiratory positive airway pressure (EPAP) with a further reduction of the AHI compared to the single therapy [72][73][74][75].
Although nasal CPAP is the standard treatment for OSA, the International Journal of Dentistry high pressure generated to maintain airway patency is a common complaint that negatively influences adherence to the treatment.Since MAD primarily widens the velopharyngeal segment of the upper airway (from the hard palate to the tip of the uvula), combined treatment could reduce the air pressure required to maintain the AHI values within the normal range [76].MAD could also act synergically with EPAP in reducing OSAS severity since MAD increases airway patency at the level of the velopharyngeal segment.In contrast, EPAP increases the hypopharyngeal segment's volume (from the epiglottis's tip to the vocal cords) [77].Furthermore, in those patients compliant with CPAP, the alternative use of MAD is that it represents an optimal solution while traveling instead of avoiding treatment in these circumstances.

MAD in Combination with
Positional Therapy.MAD treatment and positional therapy can be complementary in the clinical management of OSA patients, particularly in those subjects with the predominant positional component [50,52].MAD and positional therapy do not have the same effects in expanding the pharyngeal cavity.When used together, it is possible to combine the advantages of both treatments, increasing the patency of the airway.In this regard, positional therapy increases the side lying time and decreases the proportion of supine time while MAD prevents collapse of the pharyngeal airway in the supine position to further reduce overall AHI; also, MAD cannot completely counteract the effects of gravity in the supine position.Such differences suggest that the combined therapy could lead to a higher therapeutic efficacy in patients with POSA when compared to one of the treatment modalities alone.At the same time, when patients are treated with partial success with MAD therapy, the presence of POSA should be checked, and combined therapy could be suggested in eligible patients.
3.3.Indication for Appliance Design and for Targeting the Therapeutic Mandibular Advancement 3.3.1.Appliance Design.Several appliance designs are available in the market, with the primary distinction being between mono-bloc and dual-bloc devices.Both types of MAD were found to reduce sleepiness and daily symptoms equally [78][79][80][81][82].However, it is still being determined if one design is superior to the other in improving the AHI and other parameters of respiratory disturbance.The discriminating factor between both types of appliance design is the block of mouth opening during sleep, which reduces the amount of mandibular advancement set with the bite registration.In this regard, mono-bloc appliances firmly fix the position of the mandible to the maxilla.This may explain why some studies reported greater effectiveness of mono-bloc devices compared to dual-bloc devices appliances [83,84].However, using anterior elastics with dual-bloc appliances can counteract the tendency to open the mouth during sleep with a similar effect to mono-bloc devices [85,86].It is still unclear if different designs and configurations of acrylic, such as the different sites for titration screw/tool (incisor region or premolar-molar region, upper splint or lower splint in dualbloc devices), can influence the efficacy, the comfort, and the adherence to the treatment.However, dual-bloc devices with anterior protrusion units have the advantage of holding the mandible firmly in a protrusive position, avoiding backward mandibular rotation, and not requiring anterior elastics [35,87,88].Furthermore, the vertical dimension of the MAD is an important characteristic to consider since it can negatively influence the mandibular sagittal projection (clockwise rotation).No studies reported specific indications in this regard; however, appliances tested generally featured 4-5 mm of disclosure, which is the minimum thickness necessary to produce splints or mono-blocs with adequate resistance to bite forces.Another distinction is between customized and low-cost prefabricated heat-moulded appliances.Customized appliances would be more effective, rejecting the assumption that prefabricated appliances can be used as low-cost tools to predict the effectiveness of customized MAD treatment [89][90][91].Presumably, the absence of adequate teeth coverage and lack of retention would lead patients to discontinue the treatment when using heat-molded appliances.Also, the mandibular advancement with heat-molded appliances is not reproducible since it has to be determined and controlled during the fitting procedure, generating a high standard deviation of mean mandibular advancement in the included studies and influencing the data outcomes.

Targeted Mandibular Advancement.
Targeting optimal mandibular advancement is undoubtedly one of the main clinical concerns for dentists in managing OSA patients since it remains doubtful whether there is a dose-dependent relationship between the degree of advancement and treatment outcome with MADs [92][93][94][95].Studies assessing MAD effectiveness generally reported that 70%-80% of maximum mandibular protrusion significantly improved or normalized PSG parameters (AHI, ODI, and RDI) in at least 50% of the study population.Those studies comparing the treatment effectiveness according to different protrusion positions agreed that 75% was the most effective position, although the difference with the intermediate position (50%) was minimal and may represent the cutoff for treating mild OSAS (50% protrusion) and moderate OSAS (75% protrusion) [96][97][98].
Studies generally rely on subjective titration wherein the degree of mandibular advancement is progressively increased over several weeks (5-40 weeks) until an improvement or a resolution of symptoms occurs or until the patient cannot tolerate any further advancement.Studies have also used objective guided titration, which means selecting the mandibular position that has determined the abolishment of respiratory events or nonphysiologic parameters during the diagnostic instruments/ procedures (DISE, PSG, oximetry) [99,100].Objective-guided titration is more reproducible and could avoid the overextension of mandibular protrusion, which may occur with subjective titration, and that can generate discomfort and consequently less adherence to the treatment.However, discomfort could also occur at the start of the treatment when the appliance is designed with an objectively targeted mandibular position due to the lack of the possibility for gradual adaptation.From the clinical standpoint, the presumed gold-standard titration approach may entail International Journal of Dentistry an objective determination of the therapeutic mandibular advancement, achievable via a personalized titration protocol.A preference for titrable devices over fixed protrusion or mono-bloc appliances is implied in this context.To ensure optimal therapy adherence, a compromise between an effective protrusive position and patient tolerance needs to be found.It is important to target the protrusive position individually in terms of tolerability (see further query) versus efficacy.[102].TMD-related symptoms could either increase or decrease with treatment, suggesting that MAD treatment should not be considered an absolute risk factor for the development or worsening of TMD.The contrasting findings can be associated with the different etiology of painrelated TMD and intraarticular joint disorders [7].Subjects suffering from intraarticular joint disorders could benefit from MAD since the appliance acts as an anterior repositioning appliance.Instead, the same appliance can exacerbate symptoms in subjects with pain-related TMD, which reduces with time.In this regard, slow titration should be preferred to favoring the adaptation of masticatory structures to the advancement mandibular position.For the same reasons, dual-bloc titrable appliances may be preferred over fixed appliances, or, at least, it may be preferred during the period of acclimatization as a preliminary appliance to define the final mandibular position.These findings also suggest the importance of a preliminary TMD evaluation before administering MAD and the long-term monitoring for TMD symptoms and occlusal changes (overjet-overbite) that may require intermediate orthodontic treatment.

Indications for
3.4.2.Dento-Sketelal Changes.MAD can determine dentoskeletal changes equivalent to those recorded with functional appliances, although in adults [103,104].Such changes were generally observed through a follow-up period of 2-4 years [105,106].During treatment with MADs, the muscles, and the other soft tissues are stretched and try to pull the mandible back, thus transmitting a lingually directed force to the upper incisors and increasing their palatal inclination [107].Moreover, the mandible attempts to return to its baseline position, thus transmitting a labially directed force against the mandibular incisors and increasing their vestibular inclination [108].Skeletal changes could also occur with a reduction of intermaxillary sagittal discrepancy (ANB^).Both conditions determine a reduction of the overjet and overbite in the long term [105].Although the clinical relevance of these findings remains questionable in most of the included studies, this review reinforces the need for OSAS patients to receive proper information about the potential occurrence of these dentoskeletal changes [109,110].Occlusal monitoring should also be recommended, including the necessity for adjustments of prosthetic rehabilitations to maintain proper occlusal contact and function [111].
There are specific absolute contraindications to the usage of MAD.In this regard, a deeper evaluation of the oral health status is critical to evaluate and eventually manage potential side effects of the treatment [112].Adequate dentition is fundamental for the support and retention of the MAD.Insufficient retention compromises the effectiveness of the appliance and can result in discomfort and irritation of the soft tissues, leading to reduced compliance with the treatment.While there is no specific threshold for the number of missing teeth that definitively contraindicates the use of MAD, some studies suggest that having fewer than 8-10 teeth may represent an absolute contraindication, reporting these values as exclusion criteria.However, when assessing the retention of the appliance, clinicians should also take into account the specific location of the missing teeth and the adaptability of the appliance design for edentulous conditions before excluding the option of MAD treatment.For instance, if teeth are absent in the lateral-posterior area while both incisors and molars remain intact, there may be sufficient retention in comparison to an equivalent number of missing teeth concentrated solely in the anterior or posterior region.It is essential to note that individuals with compromised periodontal health are not suitable candidates for MAD due to the potential risk of aggravating the condition, leading to tooth loss and instability of the appliance.Limited maximum protrusion is another contraindication for administering MAD in OSA patients due to the intrinsic limitation of increasing the patency of the airway [113].In most of the retrieved studies, protrusion values <5-7 mm are reported as exclusion criteria.An accurate clinical examination is critical to verify if the limited protrusion is related to physiological skeletal or muscular anatomical characteristics or if it is associated with TMD and can improve after specific treatment.
As a consequence, patients should undergo oral and functional clinical examination before deciding to perform instrumental analysis for targeting mandibular advancement such as nocturnal polysomnography with MAD and sleep endoscopy and, in case of irreversible contraindications, inform the other sleep medicine specialists for appropriate treatment considerations.
3.4.4.General Considerations.The American Academy of Sleep Medicine (AASM) and the European Respiratory Society [5] recommended MAD as first-line treatment in mild and moderate OSA in patients without severe cardiovascular comorbidity and in severe OSA when CPAP treatment fails or is refused.As a result, the dental specialist is called to play a central role within the multidisciplinary OSA team, from 20 International Journal of Dentistry the diagnosis and treatment plan to the treatment stage and throughout the follow-up period.Despite the number of dentists qualified as specialists by the Dental Sleep Medicine Scientific Societies are increasing [114,115], many clinicians are still reluctant in undertaking the necessary training for treating OSA patients.Suboptimal communication between sleep physicians and dentists and cotreatment management of OSA patients seem to be the main reasons for the inability of dental sleep medicine to integrate fully with the delivery of sleep medicine [114].In this regard, the role of dentists is subordinate to sleep physicians, pulmonologists, neurologists, and otolaryngologists (due to the lack of or limited competencies in sleep disorders and respiratory functionality).The absence of close communication and a common patient-centered field could explain why clinicians are still reluctant to "go off the beaten track" of their routine clinical practice and take responsibility for the clinical management of patients suffering from OSA.The information retrieved from the included studies and collected in the form of specific clinically oriented subdomains may be helpful for dental specialists in the clinical management of OSA patients and in cooperation with the other specialists of the sleep medicine team.

Conclusions
According to the findings retrieved from the included studies, the present narrative review would suggest that: (1) The prediction of positive treatment with MAD seems to rely not on identifying a single factor but rather on identifying a clinical phenotype featuring multiple integrated characteristics.(2) In eligible patients, MAD could be used as a complementary solution with other treatment approaches (CPAP, positional therapy) to reduce apnea events within the safety range.(3) Targeted mandibular advancement, objectively recorded (i.e., via PSG or DISE) and achievable via a personalized titration protocol, could be the gold-standard titration protocol for MAD.In this context, a preference for titrable devices over fixed protrusion or mono-bloc appliances is implied.(4) Side effects of MAD, which were represented by mild occlusal problems, discomforts, tooth sensitivity, and pain/tenderness, referred to the TMJ or the masseter muscle area.Dento-skeletal changes can be considered equivalent to those recorded with the usage of functional appliances, although in adults.(5) An accurate clinical examination is critical to exclude oral baseline contro-indications to the usage of MAD.

FIGURE 1 :FIGURE 2 :
FIGURE 1: Flow-diagram showing the main treatment options for subjects affected by OSA.

TABLE 1 :
Continued.-month evaluation.Disc displacement developed in one subject in the JE-group at the 2-week and 1month evaluations and in two or three subjects in the PEgroup across evaluation periods.Chewing pain and jawopening pain in the morning at the 1-month evaluation
*Articles included from review.