Sage Journals: Discover world-class research

Abstract

External apical root resorption (EARR) is a common sequela of orthodontic treatment, although it may also occur in the absence of orthodontic treatment. The degree and severity of EARR associated with orthodontic treatment are multifactorial, involving host and environmental factors. Genetic factors account for at least 50% of the variation in EARR. Variation in the Interleukin 1 beta gene in orthodontically treated individuals accounts for 15% of the variation in EARR. Historical and contemporary evidence implicates injury to the periodontal ligament and supporting structures at the site of root compression following the application of orthodontic force as the earliest event leading to EARR. Decreased IL-1β production in the case of IL-1B (+3953) allele 1 may result in relatively less catabolic bone modeling (resorption) at the cortical bone interface with the PDL, which may result in prolonged stress concentrated in the root of the tooth, triggering a cascade of fatigue-related events leading to root resorption. One mechanism of action for EARR may be mediated through impairment of alveolar resorption, resulting in prolonged stress and strain of the adjacent tooth root due to dynamic functional loads. Future estimation of susceptibility to EARR will likely require the analysis of a suite of genes, root morphology, skeleto-dental values, and the treatment method to be used—or essentially the amount of tooth movement planned for treatment.

(I) Introduction

Basic descriptors of root resorption are based on the anatomical region of occurrence—i.e., internal root resorption and external root resorption (cervical root resorption and external apical root resorption). Additional classification may involve two types of internal resorption: root canal (internal) replacement resorption and internal inflammatory resorption. External resorption can be classified into four categories according to its clinical and histologic manifestations: external surface resorption, external inflammatory root resorption, replacement resorption, and ankylosis. External inflammatory root resorption has been further categorized into cervical resorption with or without a vital pulp (invasive cervical root resorption) and external apical root resorption (EARR) (Ne et al., 1999).

This paper reviews EARR and its association with orthodontic treatment, and examines a new paradigm for its multifactorial etiology. EARR is a frequent iatrogenic outcome associated with orthodontic treatment, especially in the maxillary incisors, and may also occur in the absence of orthodontic treatment (Harris and Butler, 1992; Harris et al., 1993). Depending on the methodology, the incidence of EARR without orthodontic treatment has been reported to range from zero to 90.5% (Brezniak and Wasserstein, 1993). From 7% to 13% of individuals who have not had orthodontic treatment show some EARR on radiographs (Rudolph, 1936; Harris et al., 1993), presumably as a function of occlusal forces. There is an association of EARR in those who have not received orthodontic treatment with missing teeth, increased periodontal probing depths, and reduced crestal bone heights (Harris et al., 1993). Individuals with bruxism, chronic nail biting, and anterior open bites with concomitant tongue thrust may also show an increased extent of EARR before orthodontic treatment (Harris and Butler, 1992). Dental trauma, especially with re-implantation of an avulsed tooth, is also associated with increased EARR (Donaldson and Kinirons, 2001). For the most part, EARR is asymptomatic unless substantial tooth structure is affected, so early detection is unlikely unless radiographs are used (Brezniak and Wasserstein, 1993, 2002b).

(II) Root Resorption and External Apical Root Resorption

EARR is the loss of root structure involving the apical region to the extent that it can be seen on standard radiographs (Fig. 1). EARR is distinct from root resorption (RR). Microscopic areas of resorption lacunae hallmark root resorption. These microscopic lesions lack clinical significance and are not detected by standard radiographs (Brezniak and Wasserstein, 1993). The resorption lacunae develop on the cementum root surface and can be visualized by histological techniques (Fig. 2). Although EARR and RR during orthodontic tooth movement are believed to be related conditions, a distinction should be made between these two conditions when incidence and prevalence are studied. Orthodontic force applied to teeth over a short period of time can produce resorption lacunae in the absence of EARR (Kvam, 1972). An increase in RR can be accomplished with increased duration of orthodontic force application and force, with the higher magnitude of moments producing exposure of root dentin (Casa et al., 2001).

EARR may occur preferentially in the apical region, since more than three-quarters of resorption lacunae occur in the apical region of the root (Henry and Weinmann, 1951), a fact that could be explained by the following: (1) Forces are concentrated at the root apex because orthodontic tooth movement is never entirely translatory, and the fulcrum is usually occlusal to the apical half of the root (Harris, 2000); (2) periodontal fibers assume a different direction in the apical end, which might explain the increased stress in the region (Henry and Weinmann, 1951); and (3) the apical third is covered with cellular cementum, whereas the coronal third is covered with acellular cementum. The active cellular cementum depends on a patent vasculature; accordingly, periapical cementum is more friable and easily injured in the case of trauma and concomitant vascular stasis (Henry and Weinmann, 1951; Baumrind et al., 1996; Harris, 2000).

(III) Incidence of EARR in Association with Orthodontic Treatment

Depending on the methods, EARR associated with orthodontic treatment has been noted to range between zero and 100% (Brezniak and Wasserstein, 1993). Although orthodontic treatment is associated with some maxillary central incisor EARR in most patients, and more than one-third of those treated experience greater than 3 mm of loss, severe EARR (more than 5 mm) occurs in 2% to 5% of the population (Taithongchai et al., 1996; Killiany, 1999).

(IV) The Effect of Tooth Movement and the Role of the PDL

The amount of orthodontic movement is positively associated with the resulting extent of EARR (DeShields, 1969; Sharpe et al., 1987; Parker and Harris, 1998). Orthodontic tooth movement, or “biomechanics”, has been found to account for approximately one-tenth to one-third of the total variation in EARR (Linge and Linge, 1991; Baumrind et al., 1996; Horiuchi et al., 1998), although, in one study (Parker and Harris, 1998), up to 90% of the variation has been attributed to the extent of tooth movement.

In turn, the required amount of tooth movement is a function of severity of malocclusion. For example, the greater the incisor overjet, the greater the amount of retraction during treatment, and the greater the amount of incisor resorption (Beck and Harris, 1994; Harris et al., 1997). Moreover, it was found that the deeper the overbite, the greater the incisor intrusion and resorption, and the greater the root resorption of the distal root of the maxillary first molar (Beck and Harris, 1994). Extraction patterns can influence the degree of EARR because of the increased tooth movement, compared with non-extraction cases, required to close extraction spaces (Blake et al., 1995; McNab et al., 2000). For example, cases in which 4 first premolars were extracted have more EARR than cases with no extractions, or only extractions of the 2 maxillary first premolars (Sameshima and Sinclair, 2001b).

The amount of time spent in orthodontic treatment can be a factor in EARR (Taithongchai et al., 1996), but not necessarily (Beck and Harris, 1994; Taner et al., 1999). Even when duration of treatment is a factor, it, along with several significant dentofacial structure measurements, does not account for enough of the observed variability to be useful as a predictor of EARR by itself (Taithongchai et al., 1996).

The suitability of the rat as a model for studying tooth movement was demonstrated almost 50 years ago (Macapanpan et al., 1954; Waldo and Rothblatt, 1954). Macapanpan and co-workers (1954) positioned elastic materials between the first and second maxillary molars, tipping the first molars mesially and the second and third molars distally. Tipping the teeth created sites of compression, where cellular death and hyalinization occurred, and tension, where cellular proliferation was observed in the periodontal ligament (PDL). Subsequent histological studies in rodents support an association between root resorption and the presence and active removal of the hyalinized tissues at the sites of compression following experimental tooth movement (Rygh, 1977; Williams, 1984; Brudvik and Rygh, 1993a,b, 1994; Hellsing and Hammarström, 1996). Normal healthy PDL may modulate the cascade of root resorption. Cultured primary dentition PDL fibroblasts have been shown to inhibit the differentiation of osteoclast-like cells in mouse bone marrow cultures (Wu et al., 1999). Root resorption therefore may require damage to the cementoblastic layer in combination with necrosis or inflammation. Interestingly, when orthodontic force is stopped, root resorption continues until a functional PDL is established (Brudvik and Rygh, 1995a,b).

(V) Influence of Dental Anomalies and Root Morphology

While Kjaer (1995) suggested, as risk factors, the increased prevalence (as compared with published population frequencies) of dental anomalies-such as tooth agenesis, peg-shaped or small maxillary lateral incisor crown, crown invaginations, ectopic eruption, and taurodontism-in a sample of 107 orthodontic cases presenting with “excessive” (more than one-third of one or more roots resorbed during treatment) EARR, Lee et al. (1999) did not find increased EARR in 84 orthodontic cases exhibiting at least one dental anomaly, compared with 84 matched cases in which there were no dental anomalies. The presence of more than one dental anomaly did not appear to be associated with a greater risk of EARR. The divergent outcomes may be due to the difference in the ascertainment of the study sample as well as other aspects of the two investigations.

Root length and shape have also been variables that have been studied for their association with EARR. It has been suggested that teeth exhibiting relatively short roots prior to orthodontic treatment tend to develop more resorption during orthodontic treatment (Ketcham, 1929; Becks, 1936; Massler and Malone, 1954; Massler and Perreault, 1954; Jakobsson and Lind, 1973; Goldson and Henrikson, 1975; Newman, 1975; Kjaer, 1995; Taithongchai et al., 1996; Harris et al., 1997; Thongudomporn and Freer, 1998). Even though some have inferred that this is due to increased root resorption activity prior to the orthodontic treatment, it is not clear that all relatively short roots prior to orthodontic treatment are the result of active pre-treatment resorption.

Although it has been held that a valid prognosis can be made by the clinician as to the amount of EARR that could be expected in the majority of cases on the basis of a careful analysis of relatively short pre-treatment root lengths on the radiographs taken before treatment (Massler and Malone, 1954), it has also been said that EARR does not increase in teeth with short roots (Levander and Malmgren, 1988; Goldin, 1989), or that the tendency for EARR increases with increasing tooth length (Mirabella and Årtun, 1995; Sameshima and Sinclair, 2001a). The latter finding may be related to longer teeth needing stronger forces to be moved, and the fact that the actual displacement of the root apex is larger during tipping or torquing movements of longer teeth, although the apical shortening that occurs in the shorter root is of greater concern (Mirabella and Årtun, 1995; Sameshima and Sinclair, 2001a).

The two-dimensional shape of the root as delineated on radiographic film appears to be associated with various amounts of EARR. The tendency for EARR was found to be greater in teeth with pipette-shaped roots and apical bends (Newman, 1975; Levander and Malmgren, 1988; Kjaer, 1995), bottleneck roots (McFadden et al., 1989), abnormal (pointed, eroded, blunt, bent, and bottle shape) root shape (Mirabella and Årtun, 1995), thin or pipette-shaped roots (Thongudomporn and Freer, 1998), and dilacerated, bottle-shaped, or pointed roots (Sameshima and Sinclair, 2001a), although so far there is no systematic way to estimate the likelihood of EARR based upon root shape other than to say it is increased. Teeth with blunted roots have been found to be associated with both an increased (Thongudomporn and Freer, 1998) and a decreased (Sameshima and Sinclair, 2001a) occurrence of EARR. Overall, the shape of the root does appear to be associated with the likelihood of EARR, and is best examined on periapical rather than panoramic radiographs (Sameshima and Asgarifar, 2001).

(VI) Cellular and Molecular Mechanisms of Odontoclast/Osteoclast Regulation

Multinucleated cells referred to as “odontoclasts” resorb three dental hard tissues, i.e., cementum, dentin, and enamel. These cells have morphological and functional characteristics similar to those of bone-resorbing osteoclasts (Sahara et al., 1994, 1998). Osteoclast and odontoclast precursors originate from hemopoietic cells in the bone marrow. Osteoclast formation from hemopoietic precursors is induced by the cytokines such as macrophage colony-stimulating factor (M-CSF) and TRANCE (also called RANKL, ODF, and OPGL), a membrane-bound ligand expressed by bone marrow stromal cells (Lean et al., 2000; Tsurukai et al., 2000). Osteoclast precursors may also be recruited from the blood via activated endothelium (McGowan et al., 2001). As circulating mononuclear cells (monoctyes), these precursors can be induced to proliferate and differentiate into osteoclasts (Quinn et al., 1998; Massey and Flanagan, 1999; Fujikawa et al., 2001). Receptor activator of nuclear factor kappa B (RANK) and its ligand RANKL have been localized in odontoblasts, pulp fibroblasts, periodontal ligament fibroblasts, and in single odontoclasts, the latter finding suggesting an autocrine/paracrine role (Lössdörfer et al., 2002a,b). RANK is coded for by the TNFRSF11A gene.

Osteoclastogenesis is modulated by an inhibitor, osteoprotegerin (OPG, also called TNFRSF11B). OPG is a soluble (decoy) receptor for TRANCE and a member of the TNF receptor superfamily. Osteoclast formation and survival require and are enhanced by transforming growth factor-beta (TGF-beta), which is abundant in bone matrix. TNF-alpha can also induce osteoclast formation in vitro from bone-marrow-derived mononuclear phagocytes, especially in the presence of TGF-beta. Chambers (2000) suggests that the osteoclast is a mononuclear phagocyte directed toward a debriding function by TGF-beta, activated for this function by TRANCE, and induced to become specifically osteoclastic by the characteristics of the substrate or signals from bone cells. Interleukin 1-beta (IL-1β), a potent bone-resorptive cytokine, is a component of the complex pathways leading to root resorption. A balance between IL-1β activity and interleukin receptor antagonist (IL-1RA) may be crucial in the development of periapical lesions (Shimauchi et al., 1998). Interleukin 1 alpha (IL-1α) is also a potent bone-resorptive cytokine and has been found along with TNF-alpha in periapical lesions (Fouad, 1997).

Orthodontic force leads to microtrauma of the PDL and activation of a cascade of cellular events associated with inflammation. Orthodontically induced inflammatory root resorption (OIIRR) has been suggested (Brezniak and Wasserstein, 2002a,b).

(VII) Systemic Factors

The intimate relationship between tooth movement and root resorption suggests that factors affecting tooth movement also affect root resorption. Tooth movement and changes in periodontal tissue in response to orthodontic force in rats vary depending on the time of day the force is applied (Miyoshi et al., 2001). Other systemic factors—such as nutritional factors, metabolic bone diseases, age, and use of drugs—affect orthodontic tooth movement (Tyrovola and Spyropoulos, 2001). Cyclic changes in the estradiol level may be associated with the estrous-cycle-dependent variation in tooth movement through its effects on bone resorption (Haruyama et al., 2002), and estrogen deficiency can cause rapid orthodontic tooth movement (Yamashiro and Takano-Yamamoto, 2001). Calcitonin can inhibit odontoclast activity (Wiebkin et al., 1996). The action of calcitonin on osteoclasts occurs at later stages of osteoclast development, and it inhibits the fusion of committed pre-osteoclasts to form mature multinucleated cells. Bisphosphonates include potent inhibitors of bone resorption used to treat osteoporosis and other bone diseases. Bisphosphonates directly or indirectly induce apoptosis in osteoclasts, which may play a role in inhibition of bone resorption (Reszka et al., 1999). Odontoclasts also undergo apoptosis following exposure to bisphosphonates (Watanabe et al., 2000).

(VIII) Effects of Treatment and Technique

Although treatment and, specifically, the amount of tooth movement may contribute to EARR, a comparison of maxillary central incisor EARR among cases treated with the Tweed standard edgewise technique, the Begg lightwire technique, and the Roth-prescription straightwire technique found no difference among the techniques (Parker and Harris, 1998). However, another study did find more EARR in patients treated with Begg appliances than edgewise appliances (McNab et al., 2000). No difference was also found between patients treated with the “Speed” appliance system and those who received the edgewise straightwire appliance (Blake et al., 1995). Comparisons of different techniques may be confounded by the treatment protocols or decisions of different practitioners, since there is also variation of EARR seen among different practitioners using fixed edgewise appliances (Sameshima and Sinclair, 2001b).

(IX) Effect of Sex

Although some questionable studies have found that orthodontically treated females had a greater incidence of EARR than males (Massler and Perreault, 1954; Kjaer, 1995), several studies have found no difference in EARR between treated males and treated females (Beck and Harris, 1994; Blake et al., 1995; Parker and Harris, 1998; Harris et al., 2001; Sameshima and Sinclair, 2001a).

(X) Interindividual Variability in EARR

Historically, there has been appreciable variability among orthodontic patients in susceptibility to EARR, which might be due to a systemic or innate predisposition to resorption in permanent as well as primary teeth (Becks, 1936; Massler and Malone, 1954; Massler and Perreault, 1954; Reitan, 1957; Newman, 1975). It was proposed that when extreme susceptibility exists, severe EARR would occur even in the absence of any demonstrable causes (Massler and Perreault, 1954). An ethnic dichotomy has been reported, with Asian patients having significantly less EARR than Caucasian or Hispanic patients (Sameshima and Sinclair, 2001a). Familial clustering of EARR has been reported, although the pattern of inheritance was not clear (Newman, 1975; Harris et al., 1997). This implies that there may be a genetic component for susceptibility to EARR.

(X1) Application of Genetic Analyses to EARR

Before undertaking DNA-based studies to elucidate genetic determinants of development or disease expression, one would ideally like to infer as much as possible about the role of genetic factors in phenotypic expression on the basis of development or disease patterns within families and populations (Lander and Schork, 1994). Heritability (h ²) is defined as the proportion of the phenotypic variance attributable to genetic, as opposed to environmental, variance (factors), and its estimation is one of the first objectives in the genetic study of a quantitative trait such as EARR.

Exploration of the hypothesis of genetic influence on EARR according to the sib-pair model found moderately high heritability (h ²) for EARR. The h ² estimate averaged about 70% for the maxillary incisors and mesial and distal roots of the mandibular first molars, and this accounts for approximately half of the total phenotypic variation (Harris et al., 1997). This means that siblings experience similar levels of EARR in response to orthodontic treatment. Analysis of variable DNA markers is required to indicate which areas of the genome contain genes that are at least partly responsible for the variation seen in EARR associated with orthodontic treatment. Before embarking on DNA analysis related to EARR, we confirmed the heritability of the trait in a sample from the Graduate Orthodontic Clinic at the Indiana University School of Dentistry (unpublished observations) similar to the findings of Harris et al. (1997) (Table). The heritability estimates were significantly above zero in 3 out of the 4 roots examined, at α = 0.05. Excluding the lower incisors, where h ² = zero, the heritability estimates for EARR ranged from approximately 50% and 60% for the distal and mesial roots of the mandibular first molars, respectively, to 84% for the maxillary central incisors. These estimates are comparable with those determined by Harris et al. (1997), who suggested that a low heritability estimate for the mandibular central incisor could be due to little variation in EARR experienced in the anterior mandibular teeth. Alternatively, since the power to detect heritability decreases with increasing measurement error, it is possible that the difference in heritability estimates between the various roots could be the result of differences in measurement error among teeth. It could be that the measurement error is too high in the case of the lower incisor tooth to permit significant heritability to be detected. This is supported by the mandibular central incisor root apex being the most difficult to identify, due to the superimposition of many teeth in that region on cephalographs in our study. In either case, the lack of heritability for EARR of the mandibular incisors does not necessarily indicate that these teeth are behaving differently from the roots of the other teeth where a genetic component has been documented.

Calculation of heritability estimates is a preliminary step that should be followed by tests for causative agents. With clinical orthodontics, the preliminary goal has been to define the relative contributions of genetics and the environment.

(XII) Genetic Factors Influencing EARR

EARR is likely influenced by a combination of environmental and host factors in a multifactor cascade. Efforts to investigate host factors have focused on a possible genetic component. The intrinsic value of the laboratory mouse as a model stems from several reasons, including: linkage studies; the availability of a dense and detailed genetic map that makes gene mapping in mice practical and efficient; synteny or the genomic conservation of gene order with humans (regions of many mouse chromosomes show conservation of both linkage and gene order with various segments of human chromosomes); and high degrees of homology with human gene sequences (Meisler, 1996; Ehrlich et al., 1997; Nadeau and Dunn, 1998). In addition to the large number of available mutants and inbred strains, mice are excellent hosts for genome manipulation (i.e., transgenic and gene inactivation via gene targeting/homologous recombination). Finally, from a practical standpoint, mice can be easily and economically raised in relatively small facilities and have a short gestation and lifespan, which allows large-scale and longitudinal studies to be performed.

Al-Qawasmi et al. (unpublished observations) subjected genetically disparate inbred strains of mice to standardized orthodontic force magnitude and duration where age, gender, food, and housing were controlled and found variation in the susceptibility or resistance to root resorption attributed to orthodontic force (RRAOF), indicating that genotype is an influencing factor. Mice were grouped into resistant (A/J, C57BL/6J, and SJL/J), intermediate (C3H/HeJ and AKR/J), and susceptible (BALB/cJ, DBA/2J, and 129P3/J) strains. That study identified a seven-fold difference in susceptibility between the DBA/2J (susceptible) and A/J (resistant) mouse strains. It is anticipated that in-depth study of susceptible and resistant mouse strains will facilitate the dissection of precise molecular pathways and genetic mechanisms involved in the pathogenesis of EARR in mice and could provide new information that may contribute to our understanding of mechanisms underlying the cause of EARR in humans by orthodontic force.

(XIII) Candidate Gene Analysis

Evidence of EARR heritability in humans and genetic background in an animal model, along with the present understanding of the cellular events and molecular networks/pathways implicated in EARR, provides a starting point for the investigation of candidate genes. Linkage disequilibrium methods are becoming increasingly more important in the genetic dissection of complex traits. They facilitate evaluation of candidate polymorphisms (Spielman et al., 1993) and the fine-mapping of linked regions (Risch and Merikangas, 1996). In addition to linkage studies, one of the most common means for the evaluation of evidence of an association, or linkage disequilibrium, between a candidate gene and a phenotype of interest is the case-control design. This approach involves the collection of a sample of affected and control individuals whose allele frequencies at the polymorphism in a candidate gene are then compared. A common concern in the case-control design is the spurious detection of association due to population stratification. To avoid the pitfalls of population-based association studies, investigators developed a family-based association test, the transmission disequilibrium test (TDT) (Spielman et al., 1993). The primary advantage of the TDT is that it avoids the necessity of collecting a matched control sample. As originally proposed, the TDT analyzes a nuclear trio consisting of an affected individual and his/her parents. These three individuals are genotyped at a marker in or near the candidate gene. The alleles transmitted by the genotyped parents to the affected offspring are the “affected” sample, and the alleles not transmitted from these two parents are then used as “control” alleles. Through the use of a within-family design, the control sample of alleles is perfectly matched to the affected sample of alleles, since they are transmitted from the same two parents. Thus, spurious association results due to population stratification are avoided. This approach has been extended to allow for the analysis of linkage disequilibrium with the use of quantitative rather than qualitative phenotypes (Allison, 1997; Rabinowitz, 1997; Abecasis et al., 2000; Monks and Kaplan, 2000).

Highly significant (p = 0.0003) evidence of linkage disequilibrium of an IL-1B polymorphism with the clinical manifestation of EARR has been recently reported (Al-Qawasmi et al., 2003a). Individuals homozygous for the IL-1B (+3953) allele 1 have a 5.6-fold (95% CI, 1.9–21.2) increased risk of EARR > 2 mm as compared with individuals who are not homozygous for the IL-1B (+3953) allele 1. The IL-1B gene diallelic variation at +3953 is associated with variable IL-1β protein production (Pociot et al., 1992). Cells from individuals homozygous for IL-1B (+3953) allele 1 have reduced production of secreted IL-1β compared with individuals homozygous for IL-1B (+3953) allele 2 and even individuals heterozygous for IL-1B (+3953) alleles 1 and 2 (Pociot et al., 1992). The IL-1B polymorphism described above accounts for 15% of the total variation of maxillary incisor EARR (Al-Qawasmi et al., 2003a). Rossi et al. (1996) examined IL-1 beta and TNF-alpha production in monocytes from a group of orthodontic patients with severe root shortening and found no significant differences in mean levels between resorption and non-resorption groups. This supports the likelihood that EARR is genetically heterogeneous.

In another linkage disequilibrium study (Al-Qawasmi et al., 2003b), no evidence of linkage was found with EARR and the TNF α and TNSALP genes. Non-parametric sibling pair linkage analysis with the microsatellite marker D18S64 (tightly linked to TNFRSF11A) identified evidence of linkage (LOD = 2.5; p = 0.02) of EARR affecting the maxillary central incisor (Al-Qawasmi et al., 2003b). This indicates that the TNFRSF11A locus, or another tightly linked gene, is associated with EARR. The TNFRSF11A gene codes for the protein RANK.

(XIV) Working Hypothesis for Predisposition to EARR

IL-1β is a potent stimulus for bone resorption and osteoclastic cell recruitment during orthodontic tooth movement (Alhashimi et al., 2001). Expanding on the possible mechanism of the association of the IL-1β allele 1 and EARR, a relatively decreased IL-1β production in the case of allele 1 may result in relatively less catabolic bone modeling (resorption) at the cortical bone interface with the PDL. Stress analysis of orthodontically stimulated rat molars suggests that the initiation of mechanically induced bone resorption is due to fatigue failure within the bone itself (Katona et al., 1995; Roberts, 1999). This would suggest that a deficiency of IL-1β inhibits the resorptive response to orthodontic loads. A slower rate of bone resorption may result in a prolonged stress that is concentrated in the root of the tooth, which in turn could trigger a cascade of fatigue-related events leading to root resorption (Ketcham, 1929).

In summary, EARR may be mediated through impairment of alveolar resorption, resulting in prolonged stress and strain of the adjacent tooth root due to dynamic functional loads (Katona et al., 1995). This scenario contradicts the hypothesis that increased severity of root resorption after orthodontic treatment is related to an increase in alveolar bone resorption (Engström et al., 1988). On the contrary, root resorption may be related to reduced rates of bone resorption at the PDL interface of the root and the alveolar socket. This would result in a prolonged inductive (lag) phase associated with compressed necrotic areas in the PDL prior to alveolar bone resorption. In any event, it is likely that the genetic factors that influence EARR are heterogeneous, with different mechanisms operating in affected individuals, or even site-specific responses in the same individual.

Currently, there are no reliable markers to predict either which patients will develop EARR or the severity of EARR following orthodontic tooth movement (Vlaskalic et al., 1998). The association of the IL-1B (+3953) allele 1 and EARR, which accounts for approximately 15% of the total EARR variation seen in orthodontic patients, has emerged as a potential genetic marker (Al-Qawasmi et al., 2003a). Although the presence of particular root shapes, genetic markers, marked overjet, or the need for extractions may all be associated with an increase in the likelihood of EARR, none is sufficient, alone, to predict EARR reliably. Future analysis of all of these factors (which will also require further discovery of genetic factors such as one or more genes flanking the D18S64 polymorphism, perhaps TNFRSF11A) together should increase the validity of risk estimation, and may even, within reasonable confidence intervals, result in a prediction.

TABLE
Intraclass Correlations and Heritability Estimates for EARR

Variables^a Average Sample Size^b Intraclass Correlation, r _i h ² ^c F-ratio (model) P-value

^a EARR measurements were made to the nearest 0.1 mm with the use of a technique similar to that described previously by Harris et al. (1997).

^bAverage sibship size: number of sibships. The sample consisted of 180 orthodontic patients who had received full-banded comprehensive treatment in the Graduate Orthodontic Clinic at the Indiana University School of Dentistry. The 180 cases constituted 83 full sibling pairs (sibships).

^cData from full sib-pairs were used to calculate heritability (h ²) estimates for EARR according to formulae described by Falconer (1960).

Maxillary central incisor 2.08:82 0.420 0.840 2.5 0.0001

Mandibular central incisor 2.09:80 −0.022 0.000 1.0 0.5800

Mandibular first molar-mesial root 2.11:83 0.299 0.598 1.9 0.0010

Mandibular first molar-distal root 2.11:83 0.246 0.492 1.7 0.0070

Figure 1.
Pre- and post-treatment radiographs (A and B, respectively) of maxillary central incisors from a female patient. The treatment lasted 4 yrs. The root apices are indicated by asterisks.

Figure 2.
Histological section through a mouse maxillary first molar root tipped mesially with 25 g of orthodontic force for 9 days. Resorption lacunae are indicated by arrows.

Variables^a	Average Sample Size^b	Intraclass Correlation, r _i	h ² ^c	F-ratio (model)	P-value
^a EARR measurements were made to the nearest 0.1 mm with the use of a technique similar to that described previously by Harris et al. (1997).
^bAverage sibship size: number of sibships. The sample consisted of 180 orthodontic patients who had received full-banded comprehensive treatment in the Graduate Orthodontic Clinic at the Indiana University School of Dentistry. The 180 cases constituted 83 full sibling pairs (sibships).
^cData from full sib-pairs were used to calculate heritability (h ²) estimates for EARR according to formulae described by Falconer (1960).
Maxillary central incisor	2.08:82	0.420	0.840	2.5	0.0001
Mandibular central incisor	2.09:80	−0.022	0.000	1.0	0.5800
Mandibular first molar-mesial root	2.11:83	0.299	0.598	1.9	0.0010
Mandibular first molar-distal root	2.11:83	0.246	0.492	1.7	0.0070

Footnotes

Acknowledgements

An American Association of Orthodontists Foundation Biomedical Research Award to JKH supported this work.

References

Abecasis GR, Cardon LR, Cookson WO (2000). A general test of association for quantitative traits in nuclear families. Am J Hum Genet 66:279–292.

Al-Qawasmi RA, Hartsfield JK Jr, Everett ET, Flury L, Liu L, Foroud TM, et al. (2003a). Genetic predisposition to external root apical resorption. Am J Orthod Dentofacial Orthop 123:242–251.

Al-Qawasmi RA, Hartsfield JK Jr, Everett ET, Flury L, Liu L, Foroud TM, et al. (2003b). Genetic predisposition to external apical root resorption in orthodontic patients: linkage of chromosome-18 marker. J Dent Res 82:356–360.

Alhashimi N, Frithiof L, Brudvik P, Bakhiet M (2001). Orthodontic tooth movement and de novo synthesis of proinflammatory cytokines. Am J Orthod Dentofacial Orthop 119:307–312.

Allison DB (1997). Transmission-disequilibrium tests for quantitative traits. Am J Hum Genet 60:676–690.

Baumrind S, Korn EL, Boyd RL (1996). Apical root resorption in orthodontically treated adults. Am J Orthod Dentofacial Orthop 110:311–320.

Beck BW, Harris EF (1994). Apical root resorption in orthodontically treated subjects: analysis of edgewise and light wire mechanics. Am J Orthod Dentofacial Orthop 105:350–361.

Becks H (1936). Root resorptions and their relation to pathological bone formation. Part 1: Statistical data and Roentgenographic aspects. Int J Orthodont Oral Surg 22:445–482.

Blake M, Woodside DG, Pharoah MJ (1995). A radiographic comparison of apical root resorption after orthodontic treatment with the edgewise and speed appliances. Am J Orthod Dentofacial Orthop 108:76–84.

10.

Brezniak N, Wasserstein A (1993). Root resorption after orthodontic treatment. Part 2. Literature review. Am J Orthod Dentofacial Orthop 103:138–146.

11.

Brezniak N, Wasserstein A (2002a). Orthodontically induced inflammatory root resorption. Part I: The basic science aspects. Angle Orthod 72:175–179.

12.

Brezniak N, Wasserstein A (2002b). Orthodontically induced inflammatory root resorption. Part II: The clinical aspects. Angle Orthod 72:180–184.

13.

Brudvik P, Rygh P (1993a). The initial phase of orthodontic root resorption incident to local compression of the periodontal ligament. Eur J Orthod 15:249–263.

14.

Brudvik P, Rygh P (1993b). Non-clast cells start orthodontic root resorption in the periphery of hyalinized zones. Eur J Orthod 15:467–480.

15.

Brudvik P, Rygh P (1994). Root resorption beneath the main hyalinized zone. Eur J Orthod 16:249–263.

16.

Brudvik P, Rygh P (1995a). Transition and determinants of orthodontic root resorption-repair sequence. Eur J Orthod 17:177–188.

17.

Brudvik P, Rygh P (1995b). The repair of orthodontic root resorption: an ultrastructural study. Eur J Orthod 17:189–198.

18.

Casa MA, Faltin RM, Faltin K, Sander FG, Arana-Chavez VE (2001). Root resorptions in upper first premolars after application of continuous torque moment. Intra-individual study. J Orofac Orthop 62:285–295.

19.

Chambers TJ (2000). Regulation of the differentiation and function of osteoclasts. J Pathol 192:4–13.

20.

DeShields RW (1969). A study of root resorption in treated class ii, division i malocclusions. Angle Orthod 39:231–245.

21.

Donaldson M, Kinirons MJ (2001). Factors affecting the time of onset of resorption in avulsed and replanted incisor teeth in children. Dent Traumatol 17:205–209.

22.

Ehrlich J, Sankoff D, Nadeau JH (1997). Synteny conservation and chromosome rearrangements during mammalian evolution. Genetics 147:289–296.

23.

Engström C, Granström G, Thilander B (1988). Effect of orthodontic force on periodontal tissue metabolism. A histologic and biochemical study in normal and hypocalcemic young rats. Am J Orthod Dentofacial Orthop 93:486–495.

24.

Falconer DS (1960). Introduction to quantitative genetics. New York: Ronald Press Co.

25.

Fouad AF (1997). Il-1 alpha and TNF-alpha expression in early periapical lesions of normal and immunodeficient mice. J Dent Res 76:1548–1554.

26.

Fujikawa Y, Sabokbar A, Neale SD, Itonaga I, Torisu T, Athanasou NA (2001). The effect of macrophage-colony stimulating factor and other humoral factors (interleukin-1, -3, -6, and -11, tumor necrosis factor-alpha, and granulocyte macrophage-colony stimulating factor) on human osteoclast formation from circulating cells. Bone 28:261–267.

27.

Goldin B (1989). Labial root torque: effect on the maxilla and incisor root apex. Am J Orthod Dentofacial Orthop 95:208–219.

28.

Goldson L, Henrikson CO (1975). Root resorption during Begg treatment; a longitudinal Roentgenologic study. Am J Orthod 68:55–66.

29.

Harris EF (2000). Root resorption during orthodontic therapy. Semin Orthod 6:183–194.

30.

Harris EF, Butler ML (1992). Patterns of incisor root resorption before and after orthodontic correction in cases with anterior open bites. Am J Orthod Dentofacial Orthop 101:112–119.

31.

Harris EF, Robinson QC, Woods MA (1993). An analysis of causes of apical root resorption in patients not treated orthodontically. Quintessence Int 24:417–428.

32.

Harris EF, Kineret SE, Tolley EA (1997). A heritable component for external apical root resorption in patients treated orthodontically. Am J Orthod Dentofacial Orthop 111:301–309.

33.

Harris EF, Boggan BW, Wheeler DA (2001). Apical root resorption in patients treated with comprehensive orthodontics. J TN Dent Assoc 81:30–33.

34.

Haruyama N, Igarashi K, Saeki S, Otsuka-Isoya M, Shinoda H, Mitani H (2002). Estrous-cycle-dependent variation in orthodontic tooth movement. J Dent Res 81:406–410.

35.

Hellsing E, Hammarström L (1996). The hyaline zone and associated root surface changes in experimental orthodontics in rats: a light and scanning electron microscope study. Eur J Orthod 18:11–18.

36.

Henry JL, Weinmann JP (1951). The pattern of resorption and repair of human cementum. J Am Dent Assoc 42:270–290.

37.

Horiuchi A, Hotokezaka H, Kobayashi K (1998). Correlation between cortical plate proximity and apical root resorption. Am J Orthod Dentofacial Orthop 114:311–318.

38.

Jakobsson R, Lind V (1973). Variation in root length of the permanent maxillary central incisor. Scand J Dent Res 81:335–338.

39.

Katona TR, Paydar NH, Akay HU, Roberts WE (1995). Stress analysis of bone modeling response to rat molar orthodontics. J Biomech 28:27–38.

40.

Ketcham AH (1929). A progress report of an investigation of apical root resorption of vital permanent teeth. Int J Orthod Oral Surg Radiol 15:310–328.

41.

Killiany DM (1999). Root resorption caused by orthodontic treatment: an evidence-based review of literature. Semin Orthod 5:128–133.

42.

Kjaer I (1995). Morphological characteristics of dentitions developing excessive root resorption during orthodontic treatment. Eur J Orthod 17:25–34.

43.

Kvam E (1972). Scanning electron microscopy of tissue changes on the pressure surface of human premolars following tooth movement. Scand J Dent Res 80:357–368.

44.

Lander ES, Schork NJ (1994). Genetic dissection of complex traits. Science 265:2037–2048.

45.

Lean JM, Matsuo K, Fox SW, Fuller K, Gibson FM, Draycott G, et al. (2000). Osteoclast lineage commitment of bone marrow precursors through expression of membrane-bound trance. Bone 27:29–40.

46.

Lee RY, Årtun J, Alonzo TA (1999). Are dental anomalies risk factors for apical root resorption in orthodontic patients? Am J Orthod Dentofacial Orthop 116:187–195.

47.

Levander E, Malmgren O (1988). Evaluation of the risk of root resorption during orthodontic treatment: a study of upper incisors. Eur J Orthod 10:30–38.

48.

Linge L, Linge BO (1991). Patient characteristics and treatment variables associated with apical root resorption during orthodontic treatment. Am J Orthod Dentofacial Orthop 99:35–43.

49.

Lössdörfer S, Gotz W, Jager A (2002a). Immunohistochemical localization of receptor activator of nuclear factor kappaB (RANK) and its ligand (RANKL) in human deciduous teeth. Calcif Tissue Int 71:45–52.

50.

Lössdörfer S, Gotz W, Jager A (2002b). Localization of IL-1alpha, IL-1 RI, TNF, TNF-RI and TNF-RII during physiological drift of rat molar teeth—an immunohistochemical and in situ hybridization study. Cytokine 20:7–16.

51.

Macapanpan L, Weinmann J, Brodie A (1954). Early tissue changes following tooth movement in rats. Angle Orthod 24:79–94.

52.

Massey HM, Flanagan AM (1999). Human osteoclasts derive from CD14-positive monocytes. Br J Haematol 106:167–170.

53.

Massler M, Malone AJ (1954). Root resorption in human permanent teeth: a Roentgenographic study. Am J Orthod 40:619–633.

54.

Massler M, Perreault JG (1954). Root resorption in the permament teeth of young adults. J Dent Child 21:158–164.

55.

McFadden WM, Engström C, Engström H, Anholm JM (1989). A study of the relationship between incisor intrusion and root shortening. Am J Orthod Dentofacial Orthop 96:390–396.

56.

McGowan NW, Walker EJ, Macpherson H, Ralston SH, Helfrich MH (2001). Cytokine-activated endothelium recruits osteoclast precursors. Endocrinology 142:1678–1681.

57.

McNab S, Battistutta D, Taverne A, Symons AL (2000). External apical root resorption following orthodontic treatment. Angle Orthod 70:227–232.

58.

Meisler MH (1996). The role of the laboratory mouse in the human genome project. Am J Hum Genet 59:764–771.

59.

Mirabella AD, Årtun J (1995). Risk factors for apical root resorption of maxillary anterior teeth in adult orthodontic patients. Am J Orthod Dentofacial Orthop 108:48–55.

60.

Miyoshi K, Igarashi K, Saeki S, Shinoda H, Mitani H (2001). Tooth movement and changes in periodontal tissue in response to orthodontic force in rats vary depending on the time of day the force is applied. Eur J Orthod 23:329–338.

61.

Monks SA, Kaplan NL (2000). Removing the sampling restrictions from family-based tests of association for a quantitative-trait locus. Am J Hum Genet 66:576–592.

62.

Nadeau JH, Dunn PJ (1998). Genomic strategies for defining and dissecting developmental and physiological pathways. Curr Opin Genet Dev 8:311–315.

63.

Ne RF, Witherspoon DE, Gutmann JL (1999). Tooth resorption. Quintessence Int 30:9–25.

64.

Newman WG (1975). Possible etiologic factors in external root resorption. Am J Orthod 67:522–539.

65.

Parker RJ, Harris EF (1998). Directions of orthodontic tooth movements associated with external apical root resorption of the maxillary central incisor. Am J Orthod Dentofacial Orthop 114:677–683.

66.

Pociot F, Molvig J, Wogensen L, Worsaae H, Nerup J (1992). A TaqI polymorphism in the human interleukin-1 beta (IL-1 beta) gene correlates with IL-1 beta secretion in vitro. Eur J Clin Invest 22:396–402.

67.

Quinn JM, Neale S, Fujikawa Y, McGee JO, Athanasou NA (1998). Human osteoclast formation from blood monocytes, peritoneal macrophages, and bone marrow cells. Calcif Tissue Int 62:527–531.

68.

Rabinowitz D (1997). A transmission disequilibrium test for quantitative trait loci. Hum Hered 47:342–350.

69.

Reitan K (1957). Some factors determining the evaluation of forces in orthodontics. Am J Orthod 43:32–45.

70.

Reszka AA, Halasy-Nagy JM, Masarachia PJ, Rodan GA (1999). Bisphosphonates act directly on the osteoclast to induce caspase cleavage of mst1 kinase during apoptosis. A link between inhibition of the mevalonate pathway and regulation of an apoptosis-promoting kinase. J Biol Chem 274:34967–34973.

71.

Risch N, Merikangas K (1996). The future of genetic studies of complex human diseases. Science 273:1516–1517.

72.

Roberts WE (1999). Bone dynamics of osseointegration, ankylosis, and tooth movement. J IN Dent Assoc 78:24–32.

73.

Rossi M, Whitcomb S, Lindemann R (1996). Interleukin-1 beta and tumor necrosis factor-alpha production by human monocytes cultured with l-thyroxine and thyrocalcitonin: Relation to severe root shortening. Am J Orthod Dentofacial Orthop 110:399–404.

74.

Rudolph CE (1936). A comparative study in root resorption in permanent teeth. J Am Dent Assoc 23:822–826.

75.

Rygh P (1977). Orthodontic root resorption studied by electron microscopy. Angle Orthod 47:1–16.

76.

Sahara N, Okafuji N, Toyoki A, Ashizawa Y, Deguchi T, Suzuki K (1994). Odontoclastic resorption of the superficial nonmineralized layer of predentine in the shedding of human deciduous teeth. Cell Tissue Res 277:19–26.

77.

Sahara N, Ashizawa Y, Nakamura K, Deguchi T, Suzuki K (1998). Ultrastructural features of odontoclasts that resorb enamel in human deciduous teeth prior to shedding. Anat Rec 252:215–228.

78.

Sameshima GT, Asgarifar KO (2001). Assessment of root resorption and root shape: periapical vs panoramic films. Angle Orthod 71:185–189.

79.

Sameshima GT, Sinclair PM (2001a). Predicting and preventing root resorption: Part I. Diagnostic factors. Am J Orthod Dentofacial Orthop 119:505–510.

80.

Sameshima GT, Sinclair PM (2001b). Predicting and preventing root resorption: Part II. Treatment factors. Am J Orthod Dentofacial Orthop 119:511–515.

81.

Sharpe W, Reed B, Subtelny JD, Polson A (1987). Orthodontic relapse, apical root resorption, and crestal alveolar bone levels. Am J Orthod Dentofacial Orthop 91:252–258.

82.

Shimauchi H, Takayama S, Imai-Tanaka T, Okada H (1998). Balance of interleukin-1 beta and interleukin-1 receptor antagonist in human periapical lesions. J Endod 24:116–119.

83.

Spielman RS, McGinnis RE, Ewens WJ (1993). Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 52:506–516.

84.

Taithongchai R, Sookkorn K, Killiany DM (1996). Facial and dentoalveolar structure and the prediction of apical root shortening. Am J Orthod Dentofacial Orthop 110:296–302.

85.

Taner T, Ciger S, Sencift Y (1999). Evaluation of apical root resorption following extraction therapy in subjects with class I and class II malocclusions. Eur J Orthod 21:491–496.

86.

Thongudomporn U, Freer TJ (1998). Anomalous dental morphology and root resorption during orthodontic treatment: a pilot study. Aust Orthod J 15:162–167.

87.

Tsurukai T, Udagawa N, Matsuzaki K, Takahashi N, Suda T (2000). Roles of macrophage-colony stimulating factor and osteoclast differentiation factor in osteoclastogenesis. J Bone Miner Metab 18:177–184.

88.

Tyrovola JB, Spyropoulos MN (2001). Effects of drugs and systemic factors on orthodontic treatment. Quintessence Int 32:365–371.

89.

Vlaskalic V, Boyd RL, Baumrind S (1998). Etiology and sequelae of root resorption. Semin Orthod 4:124–131.

90.

Waldo CM, Rothblatt JM (1954). Histologic response to tooth movement in the laboratory rat: procedure and preliminary observations. J Dent Res 33:481–486.

91.

Watanabe J, Amizuka N, Noda T, Ozawa H (2000). Cytochemical and ultrastructural examination of apoptotic odontoclasts induced by bisphosphonate administration. Cell Tissue Res 301:375–387.

92.

Wiebkin OW, Cardaci SC, Heithersay GS, Pierce AM (1996). Therapeutic delivery of calcitonin to inhibit external inflammatory root resorption. I. Diffusion kinetics of calcitonin through the dental root. Endod Dent Traumatol 12:265–271.

93.

Williams S (1984). A histomorphometric study of orthodontically induced root resorption. Eur J Orthod 6:35–47.

94.

Wu YM, Richards DW, Rowe DJ (1999). Production of matrix-degrading enzymes and inhibition of osteoclast-like cell differentiation by fibroblast-like cells from the periodontal ligament of human primary teeth. J Dent Res 78:681–689.

95.

Yamashiro T, Takano-Yamamoto T (2001). Influences of ovariectomy on experimental tooth movement in the rat. J Dent Res 80:1858–1861.