Introduction
The objective of this study was to investigate the association between incisor crowding, irregularity, and periodontal disease progression in the anterior teeth.
Methods
Data collected over 35 years from men enrolled in the Veterans Affairs Dental Longitudinal Study included information concerning pocket depth and alveolar bone loss. Plaster casts of the maxillary (n = 400) and mandibular (n = 408) arches were available for baseline measurements. Periodontal disease in the anterior teeth was defined as per arch sum of pathologic pocket depth and sum of teeth with any alveolar bone loss in the anterior sextants. Incisor malalignment status was defined by the anterior tooth size-arch length discrepancy index and Little’s Irregularity Index. Adjusted mixed effects linear models computed the beta (β) estimates and 95% confidence intervals (95% CI) of the amounts of change in periodontal disease outcomes by the level of malalignment.
Results
In the anterior maxillary arch, crowding and spacing were significantly associated with an increased per-arch sum of pathologic pocket depth (β, 0.70 mm; 95% CI, 0.20-1.21, and β, 0.49 mm; 95% CI, 0.06-0.91, respectively). In the anterior mandibular arch, incisor crowding and irregularity were significantly associated with an increased per-arch sum of pathologic pocket depth (mild crowding: β, 0.47 mm; 95% CI, 0.01-0.93; severe irregularity: β, 0.94 mm; 95% CI, 0.50-1.38), and the sum number of teeth with alveolar bone loss (mild and moderate-to-severe crowding: β, 0.45 teeth; 95% CI, 0.08-0.82; and β, 0.45 teeth; 95% CI, 0.13-0.83, respectively; moderate irregularity: β, 0.34 teeth; 95% CI, 0.06-0.62).
Conclusions
Certain incisor malalignment traits (ie, maxillary incisor crowding, maxillary incisor spacing, mandibular incisor mild crowding, mandibular incisor moderate-to-severe crowding, mandibular incisor moderate irregularity, and mandibular incisor severe irregularity) are associated with significant periodontal disease progression.
Highlights
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Incisor malalignment traits and periodontal disease progression were evaluated.
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Periodontal disease progression was noted in the mandibular incisor segment.
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Certain incisor malalignment traits are risk factors for periodontal disease progression.
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Incisor malalignment impacts periodontal disease.
Periodontal disease is a major public health concern globally. In the United States, approximately 50% of the adult population (≥30 years) has periodontitis. Several risk factors have been associated with periodontal disease, and modification of these factors has an important role in treatment planning and patient management. However, because of the high prevalence of periodontitis and the importance of the identification and modification of risk factors, additional research is warranted.
One often-overlooked possible causative factor for periodontal disease is the malalignment of teeth. The mechanism by which dental irregularity and crowding affect periodontal health is intuitive because dental irregularity and crowding offer a poor environment for maintaining periodontal health and cause harm to the periodontal tissues due to food retention and subsequent plaque accumulation. This plausible mechanism typically exists in the maxillary and mandibular incisor segments.
Periodontal disease is a localized disease, and crowding or irregularity is greater in the anterior area. In the current literature, results from early cross-sectional studies that investigated the association between periodontal disease parameters and anterior irregularity or crowding were often controversial because of several factors: (1) the use of invalid indexes to measure periodontitis and malalignment (eg, composite indexes), (2) difficulty in differentiating between crowding and irregularity, and (3) large statistical variability caused by a small sample size. One cohort study showed no significant association between incisor irregularity and either pocket depth or bone loss. This study had several limitations, including a short follow-up period (140 days), small sample size (n = 50) of dental students, and the use of neither reliable nor validated methods in measuring irregularity. Although the authors of this study attempted to investigate the association between incisor irregularity and periodontal disease, its limitations did not fill the gaps in the current knowledge of identifying whether irregularity or crowding is a true risk factor for periodontal disease.
Identifying irregularity and crowding as risk factors for periodontal disease may prioritize orthodontic treatment as a preventive measure over its esthetic or functional indicators. However, this action is not easily accomplished because periodontal disease advances intermittently or in bursts. To overcome these obstacles in recognizing risk factors for periodontal disease, a longitudinal study design is needed with a long follow-up time and a relatively large sample. To the best of our knowledge, the associations between incisor irregularity, crowding, and periodontal disease have not been evaluated in a longitudinal study with a long-term follow-up. Therefore, the objective of this retrospective cohort study was to investigate the association between incisor crowding, irregularity, and periodontal disease progression using rigorous longitudinal analyses.
Material and methods
In 1969, the Department of Veterans Affairs (VA) started a closed-panel dental longitudinal study by enrolling 1231 mostly white, medically healthy, community-dwelling male veterans drawn from the parallel VA Normative Aging Study. The participants had their medical and dental treatments in the private sector and were not patients of the VA care system. The first examination at which plaster casts were consistently made began in 1971. Thereafter, periodontal examinations were conducted approximately every 3 years (triennial examination) from 1971 to 2009 (total of 12 examinations). The inclusion criteria included participants who attended at least 3 examinations between 1971 and 2009, were completely dentate in the anterior sextants at baseline (1971), had measurable baseline plaster casts, and had not undergone orthodontic treatment. A retrospective sample of 400 maxillary and 408 mandibular plaster casts was available for measurements and longitudinal analysis. Mean follow-up times for subjects with maxillary and mandibular plaster casts were 23.7 ± 8.4 years and 23.5 ± 8.5 years, respectively (range, 9-36 years). All participants gave their informed consent before each examination. The study was approved by institutional review boards at Boston University Medical Center (Boston, Mass) and the VA Boston Healthcare System (Boston, Mass). This report complies with STROBE guidelines for observational studies.
At every triennial examination, calibrated periodontists performed a clinical and radiographic dental examination on all teeth and, when applicable, recorded the absence of teeth. Pocket depth and alveolar bone loss (ABL) data, limited to the anterior sextants (maxillary and mandibular central and lateral incisors and canines), were evaluated. A Williams probe (Hu-Friedy, Chicago, Ill) was used to obtain the maximum pocket depth (mesial, distal, labial, and lingual) per tooth and recorded on an interval score scale (score 1, 0-3 mm; score 2, >3-5 mm; score 3, >5 mm). The interval score scale was transformed to a continuous variable of pathologic pocket depth (PPD) in millimeters per tooth by using the midpoint of each recorded pathologic category (score 2, 4 mm; score 3, 6 mm). Afterward, the PPD in millimeters per tooth was summed per arch segment (anterior maxillary and mandibular sum of PPD). Periapical radiographs were taken with a paralleling method with Rinn holders. ABL was measured with a modified Schie score, which superimposed a translucent ruler on the radiograph with assigned reference points at the cementoenamel junction and root apex. ABL scoring was done in the interproximal sites in 20% increments (score 0, no bone loss; score 1, bone loss ≤20%; score 2, bone loss >20% to ≤40%; score 3, bone loss >40% to ≤60%, score 4, bone loss >60% to ≤80%, score 5, bone loss >8,%). For ABL, the interval score scale was transformed into a continuous variable by calculating the total number of teeth with any bone loss (ABL score 1 or higher) per arch segment. Based on repeated assessments, reproducibility of pocket depth and ABL scores indicated good reliability (>0.4 kappa statistics) in 24 participants and 25 participants, respectively. More detailed descriptions on the reproducibility of periodontal measures in the dental longitudinal study data have been reported previously.
In addition, after the teeth were rinsed with a disclosing agent, an ordinal scale was used to record plaque (score 0, none; score 1, interproximal surfaces only; score 2, interproximal surfaces continuing onto labial or lingual sites; score 3, all surfaces covering more than two-thirds of the tooth). Supragingival calculus was measured by an ordinal scale (score 0, none; score 1, discontinuous flecks; score 2, noncontinuous band on tooth surfaces; score 3, continuous band on tooth surfaces). Instrument handles were used to assess mobility by pressing on the buccal and lingual surfaces of the tooth, and movement was scored by an ordinal scale (score 0, none; score 1, <0.5 mm; score 2, 0.5-1.0 mm; score 3, >1.0 mm). For each anterior sextant, we calculated the mean plaque, calculus, and mobility scores.
Plaster dental casts obtained at baseline were used to measure incisor crowding and irregularity in the anterior maxillary and mandibular arches. In each arch, the space available minus the space required represented the amount of anterior dental crowding, as per the anterior tooth size-arch length discrepancy index. Space required was obtained by the sum of the maximum mesiodistal widths of anterior teeth, canine to canine, using a digital caliper (maximum error, 0.02 mm; Pro-Max Electronic Digital Caliper; Fowler High Precision, Newton, Mass). Available space was determined through the arch best fit using a flexible ruler from the maximum point of the canines distally. The flexible ruler was placed on the incisor surfaces of each arch, and the arch best fit was identified as the even curve accommodating most teeth. When an equal number of anterior teeth were displaced in a different manner (eg, 3 anterior teeth displaced labially, and 3 anterior teeth displaced lingually), a midpoint curve was used as a guide for the arch best fit. The severity of incisor crowding was categorized using the Index of Orthodontic Treatment Need (spacing, >0 mm; ideal alignment, 0 mm; mild crowding, <0 to ≥ −2 mm; moderate-to-severe crowding, < −2 mm). In the maxillary arch, any crowding less than 0 mm was grouped into 1 category because of the limited number of severe cases. Incisor irregularity was determined by using Little’s Irregularity Index, which defines irregularity as the labiolingual linear displacement of anatomic contact points obtained with a digital caliper placed parallel to the occlusal plane. The severity of incisor irregularity was modified into 3 categories (no-to-mild irregularity, ≥0 to <4 mm; moderate irregularity, ≥4 to ≤6 mm; severe irregularity, >6 mm). Changes in incisor crowding and irregularity status over time in the maxillary and mandibular arches were not statistically significant as tested ( P >0.05; paired t test) in a convenience sample of 39 subjects (paired t test power, 90%) who had 9 to 10 years of follow-up casts after the baseline records. After an interval of 4 weeks between measurements, intrarater reliability of more than 10% of randomly selected dental casts showed excellent interclass correlations greater than 0.98 for all 4 predictors (maxillary incisor crowding, mandibular incisor crowding, maxillary incisor irregularity, and mandibular incisor irregularity). All measurements were made by the same author (A.A.A.), who was trained by a board-certified orthodontist (L.W.).
Covariates included age in years, baseline income level (low, <$20,000; middle, ≥$20,000 to <$30,000; high, ≥$30,000), educational level (high school or some college, college graduate), smoking status (yes or no), number of medications, flossing (never or at least once a month), brushing (once a week or less, twice a week or more), quality and quantity of saliva (limited, copious), any gum treatment in the past year (yes or no), any prophylaxis cleanings in the past year (yes or no), number of teeth remaining in each anterior arch, and number of teeth remaining in the whole mouth.
Statistical analysis
All statistical analyses were conducted using software (version 9.4; SAS, Cary, NC). Analysis of variance with post hoc Tukey and chi-square tests were used in the bivariate analysis to identify any statistical association between baseline characteristics and malalignment traits as evaluated by Little’s Irregularity Index and tooth size-arch length discrepancy. Multivariate linear mixed effects models were used to estimate the effect of incisor irregularity and crowding (Little’s Irregularity Index and tooth size-arch length discrepancy) on the progression of periodontitis (sum of PPD in millimeters and number of teeth with ABL) in each arch. Correlated outcome data were controlled for by using a repeated-measure model with an autoregressive within-subject correlation matrix and a time factor (examination cycle) to cluster the observations. Confounders were included if they were significant at a 0.05 level or if they altered the coefficient of the main variable by more than 10% when the main association was significant. Statistical significance was evaluated at the 0.05 level.
Results
The unit of analysis was each anterior sextant separately (anterior maxillary arch and anterior mandibular arch). For all 4 predictors, in general, participants were self-motivated and healthy white men in their sixth decade, mostly college educated, with an income category between $15,000 and $24,999; and had no smoking habits, fairly adequate flossing and brushing practices, copious amount of saliva, and high prophylaxis treatment in the past year. Anterior sum plaque and calculus scores were higher in the mandibular anterior arch (11.6 ± 3.4 and 9.7 ± 4.5, respectively) than in the maxillary anterior arch (7.4 ± 3.6 and 3.8 ± 4.3, respectively). Anterior mobility scores were higher in the anterior maxillary arch (0.7 ± 1.7) than in the anterior mandibular arch (0.3 ± 1.3). Periodontal health outcomes in the anterior maxillary arch showed the following variations: the sum of the PPD varied from 0 to 18 mm (mean, 1.9 ± 3.5 mm), and the sum number of teeth with ABL varied from 0 to 6 (mean, 2.0 ± 2.2). Periodontal health outcomes in the anterior mandibular arch showed the following variations: the sum of the PPD varied from 0 to 17 mm (mean, 1.4 ± 2.8 mm), and the sum number of teeth with ABL varied from 0 to 6 (mean, 3.2 ± 2.3). Baseline characteristics by crowding and irregularity status of the study sample are given in Tables I through IV .
| Characteristic | Spacing: >0 mm (n = 192) |
Ideal alignment: 0 mm (n = 117) |
Crowding: <0 mm (n = 91) |
|---|---|---|---|
| Age (y), mean ± SD | 49.4 ± 7.6 | 49.4 ± 7.3 | 49.4 ± 7.2 |
| Number of teeth remaining, mean ± SD | 24.1 ± 2.9 ∗ † | 24.9 ± 2.9 | 25.1 ± 2.2 |
| Number of medications used, mean ± SD | 1.5 ± 1.4 | 1.5 ± 2.9 | 1.6 ± 1.5 |
| Baseline income (%) ‡ | |||
| ≤$14,999 | 34.6 | 31.3 | 37.9 |
| $15,000-$24,999 | 48.1 | 47.8 | 49.4 |
| ≥$25,000 | 17.3 | 20.9 | 12.6 |
| Educational level (%) ‡ | |||
| High school or some college | 30.7 | 22.2 | 24.2 |
| College graduate | 69.3 | 77.8 | 75.8 |
| Smoking status (%) | |||
| Nonsmoker | 68.8 | 69.2 | 69.2 |
| Smoker | 31.2 | 30.8 | 30.8 |
| Flossing frequency (%) | |||
| Never | 44.3 | 41.9 | 42.9 |
| At least once monthly | 55.7 | 58.1 | 57.1 |
| Brushing frequency (%) ‡ | |||
| Once a week or less | 32.5 | 36.8 | 53.9 |
| Twice a week of more | 67.5 | 63.2 | 46.1 |
| Saliva (%) ‡ | |||
| Limited | 19.8 | 11.1 | 26.4 |
| Copious | 80.2 | 88.9 | 73.6 |
| Prophylaxis in past year (%) | 66.2 | 66.7 | 70.3 |
| Gum treatment in the past year (%) | 6.8 | 6.8 | 6.6 |
| Maxillary anterior plaque index, mean ± SD | 7.6 ± 3.7 | 7.4 ± 3.5 | 7.6 ± 3.5 |
| Maxillary anterior calculus index, mean ± SD | 3.8 ± 4.4 ∗ | 3.2 ± 4.0 | 4.0 ± 4.0 ∗ |
| Maxillary anterior mobility, mean ± SD | 0.8 ± 2.0 ∗ † | 0.6 ± 1.5 | 0.4 ± 1.2 ∗ |
| Maxillary anterior sum of PPD, mean ± SD | 2.1 ± 3.9 ∗ | 1.0 ± 2.0 | 2.2 ± 3.7 ∗ |
| Maxillary anterior sum number of teeth with bone loss, mean ± SD | 2.0 ± 2.2 ∗ | 1.8 ± 2.1 | 2.0 ± 2.3 |
∗ Different from ideal alignment, P <0.05, based on analysis of variance
† Different from crowding, P <0.05, based on analysis of variance
‡ Difference between the levels of alignment, P <0.05, based on the chi-square statistic.
| Characteristics | No-to-mild: ≥0 but <4 mm (n = 272) |
Moderate: ≥4 but ≤6 mm (n = 81) |
Severe: >6 mm (n = 47) |
|---|---|---|---|
| Age (y), mean ± SD | 49.3 ± 7.8 | 50.3 ± 7.0 ∗ | 48.2 ± 8.1 ∗ † |
| Number of teeth remaining, mean ± SD | 24.5 ± 2.7 | 24.6 ± 2.9 | 24.6 ± 2.9 |
| Number of medications used, mean ± SD | 1.5 ± 1.5 | 1.6 ± 1.5 ∗ | 1.6 ± 1.5 |
| Baseline income (%) ‡ | |||
| ≤$14,999 | 35.9 | 31.7 | 30.2 |
| $15,000-$24,999 | 46.4 | 58.2 | 41.9 |
| ≥$25,000 | 17.7 | 10.1 | 27.9 |
| Educational level (%) ‡ | |||
| High school or some college | 26.1 | 25.9 | 31.9 |
| College graduate | 73.9 | 74.1 | 68.1 |
| Smoking status (%) | |||
| Nonsmoker | 68.8 | 70.4 | 68.1 |
| Smoker | 31.3 | 29.4 | 31.9 |
| Flossing frequency (%) ‡ | |||
| Never | 43.8 | 38.3 | 48.9 |
| At least once a month | 56.2 | 61.7 | 51.1 |
| Brushing frequency (%) | |||
| Once a week or less | 38.4 | 37.0 | 42.6 |
| Twice a week of more | 61.6 | 63.0 | 57.4 |
| Saliva (%) ‡ | |||
| Limited | 17.6 | 22.2 | 19.1 |
| Copious | 82.4 | 77.8 | 80.9 |
| Prophylaxis in past year (%) ‡ | 65.8 | 66.7 | 76.7 |
| Gum treatment in the past year (%) ‡ | 8.1 | 1.2 | 8.5 |
| Maxillary anterior plaque index, mean ± SD | 7.3 ± 3.6 | 7.7 ± 3.5 ∗ | 8.3 ± 3.4 ∗ † |
| Maxillary anterior calculus index, mean ± SD | 3.4 ± 4.2 | 4.5 ± 4.6 ∗ | 3.5 ± 3.2 † |
| Maxillary anterior mobility, mean ± SD | 0.7 ± 1.7 | 0.6 ± 1.4 | 0.6 ± 1.9 |
| Maxillary anterior sum of PPD, mean ± SD | 1.7 ± 3.1 | 2.1 ± 4.2 ∗ | 2.0 ± 3.4 |
| Maxillary anterior sum number of teeth with bone loss, mean ± SD | 1.9 ± 2.2 | 2.0 ± 2.1 | 2.1 ± 2.3 |
∗ Different from no-to-mild category, P <0.05, based on analysis of variance
† Different from Moderate category, P <0.05, based on analysis of variance
‡ Difference between the levels of alignment, P <0.05, based on the chi-square statistic.
| Characteristics | Spacing: >0 mm (n = 96) |
Ideal alignment: 0 mm (n = 76) |
Mild crowding: ≥–2 but <0 mm (n = 135) |
Moderate-to-severe crowding:<–2 mm (n = 101) |
|---|---|---|---|---|
| Age (y), mean ± SD | 49.5 ± 7.5 ∗ | 47.9 ± 7.8 | 50.0 ± 8.0 ∗ | 50.0 ± 7.3 ∗ |
| Number of teeth remaining, mean ± SD | 24.2 ± 3.1 ∗ ‡ | 24.6 ± 3.0 | 24.4 ± 2.7 | 24.9 ± 2.6 ∗ † |
| Number of medications used, mean ± SD | 1.7 ± 1.7 † | 1.5 ± 1.4 | 1.3 ± 1.4 ∗ | 1.6 ± 1.5 † |
| Baseline income (%) § | ||||
| ≤$14,999 | 34.4 | 29.7 | 37.9 | 32.6 |
| $15,000-$24,999 | 50.0 | 47.3 | 47.7 | 48.0 |
| ≥$25,000 | 15.6 | 23.0 | 14.4 | 19.4 |
| Educational level (%) § | ||||
| High school or some college | 29.2 | 27.6 | 28.9 | 19.8 |
| College graduate | 70.8 | 72.4 | 71.1 | 80.2 |
| Smoking status (%) § | ||||
| Nonsmoker | 63.5 | 64.5 | 72.6 | 72.3 |
| Smoker | 36.5 | 35.5 | 27.4 | 27.7 |
| Flossing frequency (%) § | ||||
| Never | 51.0 | 39.5 | 45.9 | 36.6 |
| At least once a month | 49.0 | 60.5 | 54.1 | 63.4 |
| Brushing frequency (%) § | ||||
| Once a week or less | 37.5 | 38.2 | 35.1 | 41.6 |
| Twice a week of more | 62.5 | 61.8 | 64.9 | 58.4 |
| Saliva (%) § | ||||
| Limited | 25.0 | 13.2 | 13.3 | 24.8 |
| Copious | 75.0 | 86.8 | 86.7 | 75.2 |
| Prophylaxis in past year (%) § | 72.9 | 61.8 | 68.9 | 65.4 |
| Gum treatment in the past year (%) § | 7.3 | 2.6 | 8.9 | 6.9 |
| Mandibular anterior plaque index, mean ± SD | 10.8 ± 3.3 ∗ † ‡ | 11.3 ± 3.4 | 11.9 ± 3.5 ∗ | 12.4 ± 3.2 ∗ † |
| Mandibular anterior calculus index, mean ± SD | 8.7 ± 4.7 ∗ † ‡ | 9.5 ± 5.0 | 9.9 ± 4.3 | 10.1 ± 4.1 ∗ |
| Mandibular anterior mobility, mean ± SD | 0.5 ± 1.7 ∗ † ‡ | 0.1 ± 0.6 | 0.3 ± 1.2 ∗ | 0.1 ± 0.6 † |
| Mandibular anterior sum of PPD, mean ± SD | 1.4 ± 3.2 | 1.1 ± 2.3 | 1.5 ± 2.9 ∗ | 1.5 ± 2.5 ∗ |
| Mandibular anterior sum number of teeth with bone loss, mean ± SD | 3.2 ± 2.4 ∗ † ‡ | 2.8 ± 2.3 | 3.4 ± 2.2 ∗ | 3.5 ± 2.3 ∗ |
∗ Different from ideal alignment, P <0.05, based on analysis of variance
† Different from mild crowding, P <0.05, based on analysis of variance
‡ Different from moderate-to-severe crowding, P <0.05, based on analysis of variance
§ Difference between the levels of alignment, P <0.05, based on the chi-square statistic.
| Characteristics | No-to-mild:≥0 but <4 mm (n = 205) |
Moderate:≥4 but ≤6 mm (n = 132) |
Severe: >6 mm (n = 71) |
|---|---|---|---|
| Age (y), mean ± SD | 50.0 ± 7.7 | 50.5 ± 7.7 ∗ | 49.3 ± 7.6 † |
| Number of teeth remaining, mean ± SD | 24.4 ± 2.8 | 24.5 ± 3.1 | 24.7 ± 2.8 ∗ |
| Number of medications used, mean ± SD | 1.5 ± 1.5 | 1.5 ± 1.4 | 1.5 ± 1.5 |
| Baseline income (%) ‡ | |||
| ≤$14,999 | 30.9 | 38.7 | 36.9 |
| $15,000-$24,999 | 49.3 | 50.8 | 48.1 |
| >$25,000 | 19.9 | 10.5 | 15 |
| Educational level (%) ‡ | |||
| High school or some college | 29.8 | 25.0 | 23.5 |
| College graduate | 70.2 | 75.0 | 76.5 |
| Smoking status (%) ‡ | |||
| Nonsmoker | 65.4 | 70.5 | 73.0 |
| Smoker | 34.6 | 29.5 | 27.0 |
| Flossing frequency (%) ‡ | |||
| Never | 47.3 | 40.2 | 42.2 |
| At least once a month | 52.7 | 59.8 | 57.8 |
| Brushing frequency (%) | |||
| Once a week or less | 36.8 | 39.4 | 38.8 |
| Twice a week of more | 63.7 | 60.6 | 61.2 |
| Saliva (%) ‡ | |||
| Limited | 18.5 | 17.4 | 19.4 |
| Copious | 81.5 | 82.6 | 80.6 |
| Prophylaxis in past year (%) ‡ | 65.4 | 75.8 | 69.9 |
| Gum treatment in the past year (%) | 6.8 | 7.6 | 7.1 |
| Mandibular anterior plaque index, mean ± SD | 11.1 ± 3.7 † | 11.9 ± 3.2 ∗ | 12.6 ± 3.2 ∗ † |
| Mandibular anterior calculus index, mean ± SD | 9.3 ± 4.7 | 9.6 ± 4.5 | 10.5 ± 4.3 ∗ † |
| Mandibular anterior mobility, mean ± SD | 0.2 ± 1.1 | 0.4 ± 1.3 ∗ | 0.3 ± 1.3 † |
| Mandibular anterior sum of PPD, mean ± SD | 1.2 ± 2.4 | 1.4 ± 2.9 ∗ | 1.5 ± 2.9 ∗ |
| Mandibular anterior sum number of teeth with bone loss, mean ± SD | 3.0 ± 2.3 | 3.6 ± 2.1 ∗ | 3.4 ± 2.3 ∗ † |
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