Assessing accelerated tooth movement techniques on their own catabolic merits: a review

Assessing accelerated tooth movement techniques on their own catabolic merits: a review

Journal of the World Federation of Orthodontists 7 (2018) 122e127 Contents lists available at ScienceDirect Journal of the World Federation of Ortho...

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Journal of the World Federation of Orthodontists 7 (2018) 122e127

Contents lists available at ScienceDirect

Journal of the World Federation of Orthodontists journal homepage: www.jwfo.org

Featured Review Article

Assessing accelerated tooth movement techniques on their own catabolic merits: a review Donald J. Ferguson a, *, Nikhilesh R. Vaid b, c, M. Thomas Wilcko d, e a

Professor of Orthodontics and Dean, European University College, Dubai, United Arab Emirates Professor of Orthodontics, European University College, Dubai, United Arab Emirates Private Practice in Orthodontics, Mumbai, India d Private Practice in Periodontology, Erie, Pennsylvania e Department of Periodontology, Case Western Reserve University, Cleveland, Ohio b c

a r t i c l e i n f o

a b s t r a c t

Article history: Received 25 October 2018 Received in revised form 8 November 2018 Accepted 10 November 2018

Background and Purpose: Accelerated tooth movement is facilitated by intentional injury of the periodontium followed by alveolar bone turnover, and bone biomarkers can be used to monitor bone turnover activity. The purpose of this literature review was to evaluate various surgical acceleration techniques using catabolic bone biomarkers to discriminate among rapid orthodontic techniques, such as corticotomy, micro-osteoperforations, and corticision. Methods: Scholarly literature was searched for bone marker levels associated with orthodontic surgical acceleration techniques. Key inclusion criteria were both tooth movement only (TM-O) and accelerated tooth movement (TM-A) data in the same article to normalized data per article using the fold-change concept, that is, ratio between tooth movement accelerated and tooth movement only (i.e., TM-A/TM-O). Results: Twelve publications provided bone biomarker ratio data. During 21 days following initiation of tooth movement plus corticotomy technique, tumor necrosis factor alpha (TNFa) levels elevated approximately 2.3 times greater and pre-osteoclast and/or osteoclast counts ascertained by tartrateresistant acid phosphatase (TRAP) averaged 1.5 to nearly 4.0 times greater in TM-A than TM-O. The trend demonstrated elevated catabolic biomarkers during the 2 or 3 weeks immediately following application of the TM-A technique. Conclusions: Data from bone biomarkers TRAP and TNFa clearly showed differences between TM-O and TM-A, but the differences were not enough to discriminate catabolic bone activity among the acceleration techniques corticotomy, micro-osteoperforation, and corticision. Ó 2018 Published by Elsevier Inc. on behalf of World Federation of Orthodontists.

Keywords: Orthodontics Accelerated tooth movement Bone biomarkers

1. Introduction A multitude of surgical techniques with the primary aim of accelerating orthodontic tooth movement have emerged since the 2001 reintroduction of alveolar corticotomy [1]. During the past nearly two decades, macro- and microscopic biology has demonstrated that teeth move rapidly when intentional injury to the alveolus aggravates the local bony environment resulting in

Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. Competing interests: Authors have completed and submitted the ICMJE Form for Disclosure of potential conflicts of interest. None declared. Provenance and peer review: Non-commissioned and externally peer reviewed. * Corresponding author: Dubai Healthcare City, Bldg. 27, Block D, Office 302, PO Box 53382, Dubai, United Arab Emirates. E-mail address: [email protected] (D.J. Ferguson).

increased catabolic (bone resorption and demineralization) and anabolic (bone apposition and remineralization) activities. Although current literature would suggest that any injury will accelerate clinical tooth movement, to date there has been little attempt to discriminate among acceleration techniques in a way that will benefit the clinical orthodontist. Rate of orthodontic tooth movement depends on alveolar bone modeling and remodeling (turnover) and rate of alveolar bone turnover is determined by the level of activity of bone cells (osteoclasts, osteoblasts, and osteocytes) that are under the control of mechanical and biochemical factors [2,3]. It is the increased alveolar bone turnover that reduces tooth movement resistance and facilitates accelerated tooth movement. Surgical insult affects bone around moving teeth, but beyond the notion of bone density inversely related to surgical insult [4,5], differences among various accelerated tooth movement techniques remains subject to question.

2212-4438/$ e see front matter Ó 2018 Published by Elsevier Inc. on behalf of World Federation of Orthodontists. https://doi.org/10.1016/j.ejwf.2018.11.003

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This review was focused on accelerated orthodontic tooth movement techniques with the initial aim to compare bone tissue responses with the various surgical methods advocated in the literature. Why focus on bone tissue? Because calcified tissue is the main obstacle to orthodontic tooth movement and alveolar bone mineral status is both uniquely and directly dependent on bone turnover and variations of transient bone density change. Moreover, nuanced periodontal ligament (PDL)-driven orthodontic tooth movement is subservient to the overwhelming alveolar bone density changes resulting from surgical insult [6]. The body continually senses and autoregulates to maintain the internal environment in a stable and steady-state condition of readiness (homeostasis). A healthy skeleton is a feedbackcontrolled system that continuously integrates signals and responses that sustain its functions of delivering systemic calcium while maintaining strength. As an integral body tissue, one important bone function is structural support, and bone strength depends on the anabolic adaptability to increase mass, especially when structural support is threatened. However, the anabolic and catabolic activities of the alveolus after intentional injury increases strain of the varieties of tissues that comprise the periodontium and sets in-motion a cascade of activities eventually resulting in added strength, thereby reducing tissue strains toward steady-state levels. The local structural adaptation of bones to mechanical loads is the basis for orthopedic and orthodontic procedures [7]. Tissue strain is related to induced stress levels. For an individual who stresses himself or herself routinely with exercise, bone strain or deformation ranging from approximately 0.08% to 0.18% is induced. Under these bone strain conditions, bone apposition and bone resorption remain balanced. When induced bone stress is higher, the cascade of biochemical reactions and physiological events can produce a regional acceleratory phenomena effect that, simply put, is potentiated healing leading to woven bone production. Bone tissue strain levels exceeding 0.3% deformation or 3000 microstrain (m3) are interpreted by the body as an “SOS” signal, indicating a strain overload and a potential threat to bone strength enough that the bone may no longer maintain its support function unless strength is restored or improved immediately [6,8]. It is well established that tissue strain (deformation or physical distortion) provides dynamic alterations in extracellular matrix and cytoskeletal configurations. resulting in transduction signaling and changes in the cell’s nuclear activities [9e13]. In bone tissue, this epigenetic response (i.e., the alteration in nuclear protein matrix and eventually gene activation or suppression [14,15]) goes to the purpose of maintaining or improving strength and the continuity of the skeleton to function as structural support [9]. In the context of orthodontic tooth movement, orthodontic load-induced strain caused dynamic alterations within the extracellular matrix and within the cytoskeleton of cells in the local microenvironment. The stress-induced strain mediates the proliferation, differentiation, motility, and morphology of osteoblasts, osteoclasts, and other cells in the periodontal ligament and in the alveolar bone, as well as the production of chemokines, cytokines, and growth factors. All these together determine the balance between bone resorption and formation, thus ultimately influencing local bone modeling and remodeling that allows tooth movement in response to applied orthodontic loads [9]. Bone metabolism activity can be monitored because bone turnover markers (BTMs) are released during bone modeling and remodeling and reflect the bone activity at the cellular level [16,17]. BTMs, products of bone cell activity, are commonly subdivided into three categories: 1) bone resorption markers, 2) osteoclast regulatory proteins, and 3) bone formation markers [18]. Bone biomarkers are derived from both cortical and trabecular bone and can fortunately chronicle changes in bone turnover identifying both catabolic and anabolic activities [19]. The suitability of BTMs for

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estimating the extent of the osteogenic response at a healing site has been confirmed [20], but unfortunately, bone markers cannot serve as proxy for changes in bone strength, mineral density, or bone quality [18]. The main cell signaling molecules that are involved in bone resorption are members of the tumor necrosis factor (TNF) and TNF receptor super family [21]. TNFa is a cell signaling protein (cytokine) involved in systemic inflammation and is one of the cytokines that make up the acute phase reaction [22]. The enzyme tartrate-resistant acid phosphatase (TRAP) is an osteoclast regulatory protein and a noncollagenous bone resorption marker [18,19]. Alkaline phosphatase is a membrane-bound enzyme consisting of several isoforms that originate from multiple tissues, including bone. Alkaline phosphatase is the most commonly used surrogate measure of osteoblast activity and bone formation in clinical medicine [23]. The initial purpose of this literature review was to evaluate various surgical acceleration techniques using bone catabolic and anabolic biomarkers. It became apparent after a cursory review of literature that there were insufficient orthodontic publications related to bone anabolic biomarkers, only a few that included bone catabolic biomarkers but several related to the assessment of osteoclast regulatory proteins. Hence, the purpose of the present literature review was to compare and contrast bone catabolic activities as a function of orthodontic acceleration surgical technique. The quest was to assess for differences among acceleration techniques as described by bone biomarkers TRAP and TNFa. 2. Materials and methods 2.1. Sample Scholarly literature that was published January 2000 through September 2018 was searched to include surgical techniques for accelerated orthodontics. The electronic databases searched were Medline, PubMed Central, Scopus, Embase, and Google Scholar, in addition to a hand search. Critical inclusion criteria were as follows: 1) surgical accelerated technique used, 2) quantitative bone marker data used to assess bone turnover, and 3) data for tooth movement only and tooth movement combined with an accelerated surgical technique included for comparison. Excluded were data on distraction osteogenesis, periodontal ligament distraction, and osteotomy (Fig.1). 2.2. Procedures Information from the publications was sorted and collated as follows: author (year), technique, subjects, injury, source, biomarker, control, experimental, and comparisons to tooth movement only (Table 1). All of the studies were split-mouth designs [24e35]. In the human, dog, and rabbit investigations, dental extractions were followed by retraction or protraction of adjacent teeth into the extraction site. In the rat studies, the permanent first molar was protracted in all except one constricted [30]. Timing of data collection ranged from postsurgical day 1 to day 60 [35], but the only data collated was during a 28-day period. Catabolic data were collated from the PDL pressure-side of tooth movement and ignored from PDL tension-side [33] or medullary cavity [31,33]. As previously described, data were extracted from each study if tooth movement only (TM-O) and tooth movement accelerated (TM-A) data were available for comparison in the same investigation. Values per study period presented in the publication were calculated using the fold-change concept; that is, the ratio between TM-A and TM-O values (TM-A/TM-O). For example, if the TM-O value was 2.2 and the TM-A value was 6.6, the fold-change value was calculated as 6.6/2.2, resulting in 3.0 or 3 or 300% greater. Use of the fold-change equation eliminated the need to explain the

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Additional records identified through other sources (n = 7)

Records identified through database searching (n = 57)

Records after duplicates removed (n = 49)

Records screened (n = 49)

Records excluded (n = 30)

Full-text articles assessed for eligibility (n = 19)

Full-text articles excluded, with reasons (n = 7)

Studies included in qualitative synthesis (n = 12)

Studies included in quantitative synthesis (meta-analysis) (n = 12) Fig. 1. Flow diagram illustrating publications identified, screened, eligible, and included for quantitative synthesis for meta-analysis.

units of measure (actual or percentage) or data source (serum or gingival crevicular fluid) because each study provided the means to normalize the data. 3. Results Electronic databases produced 57 publications, with an additional 7 found by hand search; 18 full articles were assessed with 7 excluded because control data were not available in order to calculate fold-change. Data from 12 publications dated from 2000 through October 25, 2018, were included in the quantitative analysis. Research subjects were animals in all except two human investigations; rats were used in eight studies, dogs in one, and rabbits in one. Nine publications included alveolar decortication technique; micro-osteoperforations (MOPs) was included in three articles and corticision was included in two articles. Catabolic bone biomarkers included TRAP with osteoclast counts in seven publications and hematoxylin and eosin staining with osteoclast counts in three articles; catabolic bone marker TNFa was used in three articles (Fig. 1).

only on day 1, 2.4 by day 3, 2.3 by day 7, 2.0 by day 10, 3.4 by day 14, and 1.0 by day 28. Two articles reported osteoclast counts for tooth movement following corticision and the fold increase compared with TM only at day 3 was 1.8, day 14 was 2.9, day 21 was 3.8, and day 28 was 2.1. For tooth movement following micro-osteoperforations (TM þ MOPs), the fold increase in osteoclast count averaged 2.2 at day 21 for the two articles. A comparison osteoclast/pre-osteoclast count among the three surgical techniques used for acceleration tooth movement demonstrated similarities (Fig. 2). 3.2. TNFa Three publications used TNFa with consistent results for the two publications reporting TM þ Corticotomy; two articles reported a 2.5-fold increase at day-28 and in one of the articles, the same foldchange was reported at day 3 and day 7. For TM þ MOP, TNFa was reported 1.9 greater than TM only at day 1, 2.0 at day 7, and no difference at day 28 (Fig. 3). 4. Discussion

3.1. TRAP Histomorphometric counts of osteoclast and pre-osteoclast after TRAP or hematoxylin and eosin staining comprised the greatest number of publications (nine) in this study. Osteoclast count averaged 1.45 times higher in TM þ Corticotomy compared with TM

It has been nearly two decades since the publication that reintroduced alveolar corticotomy and accelerated orthodontic tooth movement [1] and stimulated professional interest in rapid orthodontics [36]. A variety of acceleration techniques have emerged as iterations of periodontally accelerated osteogenic orthodontics

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Table 1 Quantitative evaluation of 12 publications Author (year)

Technique

Subject

Injury

Source

Biomarker

Control

Experimental

Fold-change

Alikhani [24] (2013)

TM only TM þ MOPs

Human ext- ret

3 MOPs

GCF

TNFa

Teixeira [25] (2010)

TM TM TM TM

Rat

3M dots 5 mm

Human ext-ret

3B-3L-2 crest dots

mRNA histo GCF

TNFa TRAP TNFa

2.3 @ day 1 1.2 @ day 7 0.9 @ day 28 2 fold @ day 28 9 @ day 28 52.8 @ day 3 48.5 @ day 7 45.7 @ day 28 22.5 @ day 1 25.3 @ day 7 36.7 @ day 14

4.3 @ day 1 2.4 @ day 7 0.9 @ day 28 5 fold @ day 28 22 @ day 28 131.6 @ day 3 122.4 @ day 7 112.6 @ day 28 34.3 @ day 1 41.6 @ day 7 52.3 @ day 14

1.9 @ day 1 2.0 @ day 7 0 @ day 28 2.5 @ day 28 2.4 @ day 28 2.5 @ day 3 2.5 @ day 7 2.5 @ day 28 1.5 @ day 1 1.6 @ day 7 1.4 @day 14 1.55 @ day 21

[email protected] day 7 0.5 @ day 14 100% @ day 10

7 @ day 7 3.2 @ day 14 20% @ day 10

3.9 @ day 7 6.4 @ day 14 2.0 @ day 10

[email protected] day 7 al [email protected] day 14 [email protected] day 28 3.8 @ day 3 2.7 @ day 14 4.0 @ day 28 3.8 @ day 3 2.7 @ day 14 4.0 @ day 28 5.6 @day 1 5.0 @day 3 6.8 @ day 7 5 @ day 21 6 @ day 42 5 @ day 21 6 @ day 42 6.0 @ day 3 4.0 @ day 21

[email protected] day 7 [email protected] day 14 [email protected] day 28 8.2 @ day 3 7.2 @ day 14 4.7 @ day 28 9.9 @ day 3 7.8 @ day 14 8.4 @ day 28 8.0 @ day 1 12.2 @ day 3 8.6 @ day 7 14.5 @ day 21 11 @ day 42 16 @ day 21 11 @ day 42 9.5 @ day 3 3.0 @ day 21

3.5 1.5 0.7 2.2 2.7 1.2 1.8 2.9 2.1 1.4 2.4 1.3 2.9 1.8 3.8 1.8 1.6 0.8

JWFO [26] (2018)

only þ Cort only þ Cort

Chen [27] (2016)

TM only TM þ Cort

Rabbit ext-ret

3-4B-L dots

mRNA

TRAP

Cheung [28] (2016)

TM TM TM TM TM TM TM TM

Rat

5-ML dots

Histo

TRAP

Rat

4-L dots

Histo

TRAP

Rat

10P dots þ cuts

Histo

TRAP

Beagle ext-ret

Cuts BL

Histo

TRAP

Rat

3B-2P dots

Histo

TRAP

Dutra [29] (2017) Iglesias-Linare [30] (2012) Iino [31] (2007)

Perona [32] (2017)

only þ MOPs only þ Cort only þ Cort only þ Cort

TM only TM þ Cort TM þ CIncis

CInc M-D

Schneider [33] (2017)

TM only TM þ Cort

Rat

3M-3D dots

Histo

OC H&E

Tsai [34] (2016)

TM only TM þ MOPs TM þ CIncis

Rat

3P MOPs

Histo

OC H&E

TM only TM þ Cort

Rat

Histo

OC H&E

Wang [35] (2009)

1P Incision Cuts circle molar

@ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @

day day day day day day day day day day day day day day day day day day

7 14 28 3 14 28 3 14 28 1 3 7 21 42 21 42 3 21

Technique included tooth movement only (TM only), tooth movement plus corticotomy (TM þ Cort), micro-osteoperforations (TM þ MOPs), or corticision (TM þ CIncis). Nonrat subject included extraction and retraction (ext-ret); source of analysis was gingival crevicular fluid (GCF), messenger RNA (mRNA), or histomorphology (histo); biomarker used was tumor necrosis factor alpha (TNFa), tartrate-resistant acid phosphatase (TRAP), or osteoclasts with hematoxylin and eosin (OC H&E); control and experimental data units were identified by the article per day after injury; fold-change satisfied the expression experimental/control data.

with minor modifications or with major modifications of periodontally accelerated osteogenic orthodontics, such as piezocision, whereas other techniques have emerged as unique, in and of themselves, such as flapless corticision and micro-osteoperforation techniques. The concept of intentional injury to the periodontium to stimulate a biological reaction facilitating accelerated tooth

movement is viewed as intrepid by some [13], but is widely accepted as adjunctive and able to increase tooth movement efficiency [37]. Techniques used to accelerate tooth movement are well established and considered safe but not without risk. Interest in orthodontic tooth movement metabolism is strong, but the coordinated biochemical reactions, sourced in DNA, leading to

Fig. 2. Average osteoclast count fold-increases for three TM-A techniques. Osteoclast counts identified using TRAP for tooth movement þ corticotomy (TM þ Cort), þ corticision (TM þ CIncis) and þ micro-osteoperforations (TM þ MOPs) expressed as the ratio of TM-A divided by TM-O. Day-n represents the number of days since the accelerated technique (i.e., intentional surgery or injury). Note than all acceleration techniques succeeded in elevating catabolic bone activity as biomarked using TRAP.

Fig. 3. Average TNFa fold-increases for two TM-A techniques. The cytokine level for inflammation identified using TNFa was expressed as the ratio of TM-A divided by TMO. Day-n represents the number of days since the accelerated technique (i.e., intentional surgery or injury). Note than both acceleration techniques succeeded in elevating catabolic bone activity as biomarked using TNFa.

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end points of encoded protein synthesis, including inflammatory cytokines and chemokines, receptor activation, and deactivation factors indicative of both catabolic and anabolic activities is complex [38]. The number of scholarly publications describing metabolic bone biomarkers in rapid orthodontic technique is quite limited and most have been published since 2015. Evident from the results of the present study is that any intentional injury to the periodontium combined with tooth movement evoked a catabolic bone turnover increase that differed from tooth movement only. Osteoclast counts increased from 1.5 to nearly 4.0 times during the first 3 weeks after surgery when split-mouth local tissues were examined for TRAP staining histomorphometrically. TNFa levels extracted locally remained 2.5 elevated in TM þ Corticotomy through day 28, whereas TM þ MOPs levels did not exceed 2 through day 7. There are both qualitative and quantitative differences in tissue turnover that depend on the magnitude of alveolar injury (intensity) and the distance (both spatial and temporal) from the injury site [39]. Tissue strains rapidly escalate to highest immediately after intentional injury to the periodontium; turnover is greatest closest to the injury site and the time of injury (spatiotemporal) and strain then trails off over time [6,40]. There are two contrasting concepts concerning bone adaptation following intentional injury: 1) as bone gains strength, tissue strain is reduced, thereby returning to preinjury homeostatic strain values, and 2) the bone condition becomes permanently or semipermanently stronger by increased production of woven bone later replaced by lamellar bone. The first notion is homeostatic bone regulation or Frost’s mechanostat theory [30], and the second is epigenetic bone regulation suggesting that a transient change in the environment can result in a stable change of state of the system [41]. Changes in BTMs should accurately portray these changes of magnitude that are dependent on the size, extent, and temporal nature of injured bone repair, and the turnover process will influence the levels of BTMs [42]. The expected time required for a complete and adequate healing process depends on the degree of injury of the hard and adjacent soft tissue, among other factors [43,44]. Release of the broad array of active biological agents in the strained periodontium generates a complex multifactorial sequence of biological events [9], which is nothing short of complex. The molecular and nano level intricacies are fascinating but daunting and remain unclear [38,45], and thus limits the interpretation of the present results. Results of BTM assays vary depending on which subjects are used in the research (i.e., human, canine, or rodent), the magnitude of subject injury, the timing of biomarker assay relative to both the 24-hour clock, as well as the temporal distance from date of initial injury. Biological variability within the same research sample also can be a major influence on biomarker assay results, as is the variability among manufacturers providing assay kits. It also can occur due to variability in sensitivity and specificity of the assay intended to measure the same cell product target. Biomarker assay results also may be influenced by interlaboratory variability, variations in the standardization of sample processing and preservation, loss of statistical power due to the inclusion of only a small number of subjects, and analytical variability. Tooth movement is associated with expression of numerous inflammatory homeostatic chemokines (e.g., CCL2, CCL3, CCL5) and inflammatory cytokines (interleukin [IL]-1, IL-12, IL-18, TNF) without a clue toward which one exactly represents the phenomenon. Of the latter inflammatory cytokines, TNFa is one of the most commonly studied as a bone biomarker [12], and therefore was selected as a biomarker of choice for the present review. The reader needs to be cautioned that TNFa as a biomarker should not be elevated in importance relative to other biomarkers simply because there is scarcity of accelerated tooth movement biomarker research.

Local, intentional injury of the alveolus results in increased magnitude and rate of tooth movement and decreased active treatment time; these facts are clearly apparent from macro- and microscopic perspectives. Two-fold-plus increases in active clinical treatment time efficiency [37], as well as clinical tooth movement rate and magnitude [4,46], are routinely reported. Accelerated tooth movement investigation results demonstrate a spatio-temporal and proximity relationship between alveolar injury and response (i.e., greater alveolar injury promulgates greater biomarker release), resulting in greater tissue turnover, greater osteopenia (bone mineral reduction), and hence greater rate and magnitude of accelerated tooth movement [47]. Repeated alveolar injury has been reported in foxhounds [48] and humans [49,50], but effects of repeated injury on tooth movement acceleration have been reported as equivocal. If further research supports repetition of intentional injury to maintain tooth movement acceleration, micro-perforation or corticision techniques would be the methods of choice because they are less invasive and more accepted by the patient. Comparing and contrasting the three acceleration techniques featured in the present review was confounded by method differences. The corticotomy uses a full-thickness flap, facilitates direct visual access of the bone to be injured, and typically employs greater injury. Both corticision and micro-osteoperforations are flapless techniques with injury to alveolar bone made through the gingival soft tissues, and the degree on injury is typically less than corticotomy but carries no standardization on amount of injury. Although use of the fold-change concept ameliorates differences in data among techniques to some extent, data based on flap versus flapless methods and variability of injury magnitude are confounding factors. Cells sense force and convert mechanical stress into molecular signals that in turn influence the specific response of these cells to that specific force. But the complex in vivo structure of the tissues involved makes it impossible to investigate force sensing and cellular communication of individual cells. Orthodontic tooth movement involves numerous events, spatially and temporally, orchestrated and coordinated by different cell types, signaling factors, and networks [51]. To date, our understanding of the molecular and nano processes have resulted from tissue strain and epigenetic change sourced in DNA that is transcribed to messenger RNA and then to a protein/polypeptide that is subject to identification via biomarkers; however, this approach may not hold the answers [52,53]. Systematic breakdown and analysis of individual components of this complex process may be the key for understanding this molecular background in the future, but to date, has yet to provide a cohesive understanding of clinically relevant tooth movement [6]. 5. Conclusions Twelve publications provided bone biomarker data that were normalized per article using a fold-change concept. Data reported were the ratio between TM-A and TM-O (i.e., TM-A/TM-O). Results of data review demonstrated the following: 1. Pre-osteoclast and/or osteoclast counts ascertained by TRAP averaged 1.5 to nearly 4.0 times greater in TM-A than TM-O during 21 days following initiation of tooth movement plus corticotomy technique. 2. TNFa levels elevated 2.5 times greater through day 28 after initiation of tooth movement plus corticotomy technique, whereas TNFa levels elevated no greater than two times during the first 7 days in the tooth movement þ microosteoperforation technique. 3. Corticotomy combined with dental (canine or periodontal ligament) distraction is an obvious solution, but not for the

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conservative or faint-hearted clinician. If prolonged release of biomarkers is the goal, then a less invasive acceleration technique (i.e., micro-perforation or corticision) has merit. Based on the conditions of this review, data from bone biomarkers TRAP and TNFa were not enough to discriminate between the acceleration techniques using corticotomy, micro-osteoperforation, and corticision. Acknowledgments Funding was not required for this literature review study conducted in a university setting at European University College. The authors have no other financial relationships to disclose. References [1] Wilcko WM, Wilcko MT, Bouquot JE, Ferguson DJ. Rapid orthodontics with alveolar reshaping: two case reports of decrowding. Int J Periodontics Restorative Dent 2001;21:9e19. [2] Krishnan V, Davidovitch Z. On a path to unfolding the biological mechanisms of orthodontic tooth movement. J Dent Res 2009;88:597e608. [3] Krishnan V, Davidovitch Z. Biological mechanisms of tooth movement. 2nd ed. Hoboken, NJ: Wiley-Blackwell; 2015. [4] Cohen G, Campbell PM, Rossouw PE, Buschang PH. Effects of increased surgical trauma on rates of tooth movement and apical root resorption in foxhound dogs. Orthod Craniofac Res 2010;13:179e90. [5] McBride MD, Campbell PM, Opperman LA, Dechow PC, Buschang PH. How does the amount of surgical insult affect bone around moving teeth? Am J Orthod Dentofacial Orthop 2014;145:S92e9. [6] Ferguson DJ, Wilcko MT. Tooth movement mechanobiology: toward a unifying concept. In: Shroff B, editor. Biology of orthodontic tooth movementecurrent concepts and applications in orthodontic practice. Cham, Switzerland: Springer International Publishing AG; 2016. p. 13e44. [7] Harada S-I, Rodan GA. Control of osteoblast function and regulation of bone mass. Nature 2003;423:349e55. [8] Frost HM. Perspectives: bone’s mechanical usage windows. Bone Miner 1992;19:257e71. [9] Feller L, Khammissa RA, Schechter I, Moodley A, Thomadakis G, Lemmer J. Periodontal biological events associated with orthodontic tooth movement: the biomechanics of the cytoskeleton and the extracellular matrix. Sci World J 2015;894123:1e7. [10] Ingber DE. Tensegrity-based mechanosensing from macro to micro. Prog Biophys Mol Biol 2008;97:163e79. [11] Ingber DE. From cellular mechanotransduction to biologically inspired engineering. Ann Biomed Eng 2010;38:1148e61. [12] Kapoor P, Kharbanda OP, Monga N, Miglani R, Kapila S. Effect of orthodontic forces on cytokine and receptor levels in gingival crevicular fluid: a systematic review. Prog Orthod 2014;15:1e21. [13] Masella RS, Chung P-L. Thinking beyond the wire: emerging biologic relationships in orthodontics and periodontology. Semin Orthod 2008;14:290e304. [14] Masella RS, Meister M. Current concepts in the biology of orthodontic tooth movement. Am J Orthod Dentofacial Orthop 2006;129:458e68. [15] Meikle MC. The tissue, cellular, and molecular regulation of orthodontic tooth movement: 100 years after Carl Sandstedt. Eur J Orthod 2006;28:221e40. [16] Fisher A, Fisher L, Srikusalanukul W, Smith PN. Bone turnover status: classification model and clinical implications. Int J Med Sci 2018;15:323e38. [17] Yoon B-H, Yu W. Clinical utility of biochemical marker of bone turnover: Fracture risk prediction and bone healing. J Bone Metab 2018;25:73e8. [18] Cox G, Einhorn TA, Tzioupis C, Giannoudis PV. Bone-turnover markers in fracture healing. J Bone Joint Surg Br 2010;92:329e34. [19] Camassa JA, Diogo CC, Sousa CP, et al. Bone turnover markers in sheep and goat: a review of the scientific literature. An Acad Bras Cienc 2017;89:231e45. [20] Dias IR, Viegas CA, de Azevedo JT, et al. Assessment of markers of bone formation under controlled environmental factors and their correlation with serum minerals in adult sheep as a model for orthopaedic research. Lab Anim 2008;42:465e72. [21] Glendenning P, Chubb P, Vasikaran S. Clinical utility of bone turnover markers in the management of common metabolic bone diseases in adults. Clin Chim Acta 2018;481:161e70. [22] Algate K, Haynes DR, Bartold PM, Crotti TN, Cantley MD. The effects of tumour necrosis factor-a on bone cells involved in periodontal alveolar bone loss; osteoclasts, osteoblasts and osteocytes. J Periodontal Res 2016;51:549e65. [23] Vinoth JK, Patel KJ, Lih WS, Seow YS, Cao T, Meikle MC. Appliance-induced osteopenia of dentoalveolar bone in the rat: effect of reduced bone strains on serum bone markers and the multifunctional hormone leptin. Eur J Oral Sci 2013;121:517e24. [24] Alikhani M, Raptis M, Zoldan B, et al. Effect of micro-osteoperforations on the rate of tooth movement. Am J Orthod Dentofacial Orthop 2013;144:639e48.

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