Association between polymorphisms in the gene encoding parathyroid hormone and orthodontically induced external apical root resorption

Abstract

Introduction  The mechanism of action of parathyroid hormone (PTH) in bone resorption supports the idea that polymorphisms in this gene may be associated with root resorption. Therefore, this study aimed to investigate the association between polymorphisms in the gene encoding PTH and the occurrence of severe orthodontically induced external apical root resorption (OIEARR) in patients with severe skeletal malocclusion.

Methodology  This cross-sectional study involved the evaluation of panoramic radiographs from orthodontic patients and DNA extracted from saliva. Post-treatment external apical root resorption was evaluated according to the Levander and Malmgren classification. Patients exhibiting Grade 4 resorption in at least one permanent tooth were included in the case group.Three polymorphisms in the PTH gene (rs694, rs6256, and rs307247) were investigated. DNA concentration and purity were quantified using a NanoDrop spectrophotometer, and genomic DNA was subsequently genotyped for allelic discrimination using TaqMan-based real-time PCR assays. Allele and genotype frequencies were calculated. Comparisons between groups with and without severe OIEARR were performed using the chi-square test and binary logistic regression analysis with a significance level of 5%.

Results  A total of 159 patients (53 males and 106 females) were included. Most patients presented a Class III profile. Sex, age, and facial profile were not associated with severe OIEARR (p>0.05). A borderline association was observed in the allele distribution for the polymorphism rs6256 (p=0.057; OR=1.7, 95% CI=1.0–3.2). Binary logistic regression analysis did not show statistical significance (p>0.05).

Conclusion  The G allele in the rs6256 polymorphism in the PTH gene showed borderline values for severe OIEARR. The multivariable model adjusted for sex and facial profile type did not show statistical associations between the studied PTH genetic polymorphisms and OIEARR.

Keywords
Orthodontic treatment; Dental root; Gene; Polymorphism; Parathyroid hormone

Introduction

Orthodontically induced external apical root resorption (OIEARR) is one of the most commonly reported iatrogenic side effects of orthodontic movement. It is a pathological condition that may develop during or after orthodontic treatment, resulting in the permanent loss of dental structure in the apical portion of the root (cementum and dentin), thereby compromising its strength and longevity. OIEARR is characterized by an inflammatory process mediated by odontoclasts and other clastic cells.¹

Previous studies indicate that the etiology of OIEARR is multifactorial, involving a complex interplay between mechanical factors (such as deleterious habits and the intensity and duration of orthodontic treatment forces), morphological variations (including severe skeletal malocclusion, alveolar bone structure, and root morphology), and biological or genetic influences.¹-⁴ Although the etiological background is broad, growing evidence highlights the significant influence of genetic factors, as different genetic variants may modulate key pathways involved in the remodeling of dental and bone tissues during orthodontic tooth movement.⁵-⁷

Parathyroid hormone (PTH) is an 84-amino acid peptide hormone that acts as a fundamental regulator of calcium homeostasis and a mediator of bone remodeling.⁸

PTH is essential in maintaining systemic calcium homeostasis by prompting the release of calcium into the bloodstream through actions on bone and the kidneys. At the cellular level, PTH regulates bone remodeling by modulating the activity of osteoblasts (which mediate bone formation) and osteoclasts (which mediate bone resorption), while also stimulating the proliferation and differentiation of mesenchymal stem cells to support tissue regeneration.⁹ Administration of PTH promotes cementoblast-mediated cementogenesis, which may facilitate periodontal healing and the regeneration of dental roots affected by resorption.¹⁰

Active vitamin D binds to the vitamin D receptor (VDR) and directly inhibits the transcription of the PTH gene, thereby reducing parathyroid hormone levels.¹¹

Genetic polymorphisms in VDR¹²,¹³and other vitamin D-related genes¹³have previously been associated with OIEARR. An in vitro study suggested that polymorphisms in the VDR gene regulate VDR expression in periodontal ligament fibroblasts during orthodontic tooth movement.¹⁴

Vitamin D and VDR have been extensively studied in relation to orthodontic tooth movement and root resorption. Although VDR and PTH are known to be interconnected, the association between PTH and OIEARR has not yet been explored. The mechanism of action of PTH in bone resorption supports the idea that polymorphisms in this gene may be associated with root resorption. Therefore, this study aimed to investigate the association between polymorphisms in the gene encoding PTH and the occurrence of OIEARR in patients with severe skeletal malocclusion.

Methodology

Ethics and settings

This phenotypic-genetic association study with a cross-sectional design involved the evaluation of data from panoramic radiographs of orthodontic patients requiring orthognathic surgery, as well as genomic DNA extracted from saliva. This was a convenience sample.

The local Ethics Committee approved the study protocol (number: 80846317.8.0000.0093). All participants provided written informed consent to participate in the study. The recommendations of the Strengthening the Reporting of Genetic Association Studies (STREGA) checklist, an extension of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE), were followed in the study design and reporting, as recommended by Little, et al. (2009).¹⁵

Phenotype determination

The panoramic radiographs of orthodontic patients treated with fixed appliances were screened to determine their eligibility.

The inclusion criteria were adult individuals of both sexes under treatment at the University who required orthognathic surgery. The exclusion criteria were the following: diagnosed syndromes or metabolic diseases; patients with oral clefts; and patients with a history of facial trauma or previous facial surgery. Low-quality panoramic radiographic images were excluded. Additionally, teeth with previous root canal treatment or root fractures were not evaluated.

Sample size was estimated using G*Power software (version 3.1.9.7), based on a chi-square test for the association between genotypes and the categorical outcome of severe OIEARR (yes/no). Assuming a 30% prevalence of severe OIEARR in the risk genotype group and 10% in the control group, with α=0.05 and 80% power, the minimum required sample size was estimated to be 144 individuals.¹⁶

Post-treatment external apical root resorption was evaluated on digitized radiographs. The evaluation followed the protocol described by Schroder, et al. (2025).¹⁶

All maxillary and mandibular permanent teeth were evaluated for OIEARR using the Levander and Malmgren classification.¹⁷ This scale categorizes resorption into five grades: Grade 0 (no resorption), Grade 1 (irregular contour), Grade 2 (minor resorption < 2 mm), Grade 3 (moderate resorption up to one-third of the root length), and Grade 4 (severe resorption exceeding one-third of the root length). For the purposes of this study, only patients exhibiting Grade 4 resorption in at least one permanent tooth were included in the case group.

To assess intra-examiner reliability, 10 randomly selected panoramic radiographs were re-evaluated by the same senior radiologist after a two-week interval. Since root resorption was categorized dichotomously (present/absent OIEARR) based on the Malmgren index, agreement between assessments was determined using Cohen’s kappa coefficient (kappa > 0.80), indicating excellent reproducibility.

Genetic analysis

Saliva samples were collected by rinsing with 5 mL of saline solution to obtain genomic DNA. The resulting mixture was centrifuged at 550 x g for 10 minutes, and the isolated cell pellet was then resuspended in 1 mL of extraction buffer (10 mM Tris–HCl, pH 7.8; 5 mM EDTA; 0.5% SDS) and preserved at -20 °C. DNA extraction followed an established protocol,¹⁸ and its quality and concentration were verified using a NanoDrop 1000 spectrophotometer (Thermo Scientific, Waltham, USA).

Three polymorphisms in the PTH gene (rs694, rs6256, and rs307247), located on chromosome 11p15.3, were selected for this study based on a minor allele frequency (MAF) greater than 5%. The characteristics of each selected genetic polymorphism are provided in Table 1.

Table 1
Characteristics of the three PTH polymorphisms studied.a

Polymorphism	Alteration	MAFb (ALFA)c
rs307247	Downstream transcript variant	0.3954
rs6256	Stop gained Arg > Ter	0.1252
rs694	Intron variant	0.4215

• ^aSources of information: dbSNP from: ncbi.nlm.nih.gov; genome.ucsc.edu; https://www.thermofisher.com.^b Minor allele frequency.
• ^c Allele Frequency Aggregator (NCBI database of Genotypes and Phenotypes [dbGaP]).

Laboratory genotyping was conducted in a blinded manner via TaqMan real-time polymerase chain reaction (PCR) technology on a StepOnePlus system (Applied Biosystems, Foster City, USA). For quality assurance, 10% of the samples were randomly selected for duplicate genotyping, achieving 100% concordance.

Statistical analysis

The Hardy–Weinberg equilibrium was tested to ensure the reliability of the genotyping data. Descriptive statistics were used to characterize the study population in terms of age, sex, and facial profile. Missing genotype data were excluded from the statistical analysis. Allele and genotype frequencies were calculated for all three genetic polymorphisms. Comparisons of allele and genotype distributions between groups with and without severe OIEARR were performed using the chi-square test.

Binary logistic regression analysis was conducted to evaluate the association between the candidate polymorphisms and the occurrence of severe OIEARR (categorized dichotomously). The multivariable model was adjusted for potential confounding covariates, including sex and facial profile (classified as Profile I, II, or III). Crude and adjusted odds ratios (ORs), along with their corresponding 95% confidence intervals (95% CIs), were estimated.

All statistical analyses were performed using SPSS (IBM Corp. Released 2025. IBM SPSS Statistics for Windows, Version 31.0. Armonk, NY: IBM Corp), with the significance level set at α of 5%.

Results

A total of 159 patients (53 males and 106 females) were included. Their ages ranged from 17 to 57 years, with 91 patients presenting severe OIEARR and 68 without severe OIEARR. Most patients presented with a Class III profile. Sex, age, and facial profile were not associated with severe OIEARR (p>0.05).

The characteristics of the included patients are presented in Table 2.

Table 2
Characteristics of the included sample.

Variable	Without severe OIEARR n (%)	With severe OIEARR n (%)	P-value
Gender
Male	20 (37.7)	33 (62.3)	0.364*
Female	48 (45.3)	58 (54.7)
Age in years
Mean (SD)	30.25 (9.5)	31.37 (10.4)	0.480**
Type of profile
Class I	11 (16.2)	18 (19.8)	0.805*
Class II	17 (25.0)	20 (21.9)
Class III	40 (58.8)	53 (58.2)

• Note: * The chi-square was used. ** The t-test was used.

All studied genetic polymorphisms were in Hardy–Weinberg equilibrium (p>0.05).

Table 3 shows the allele distributions between the groups. A borderline statistically significant difference was observed in the allele distribution of the genetic rs6256 polymorphism (p=0.057; OR=1.7, 95% CI=1.0–3.2).

Table 3
Allele distribution between OIEARR groups.

Polymorphism	Allele	Without severe OIEARR n (%)	With severe OIEARR n (%)	P-value
rs307247	A	47 (35.1)	72 (39.5)	0.416
	G	87 (64.9)	110 (60.5)
rs6256	G	106 (79.1)	155 (87.1)	0.057
	T	28 (20.9)	23 (12.9)
rs694	C	54 (39.7)	75 (41.2)	0.787
	T	82 (60.3)	107 (58.8)

• Note: The chi-square was used.

Table 4 shows the genotype distributions between groups. No statistically significant difference was observed.

Table 4
Genotype distribution between OIEARR groups.

Polymorphism	Genotype	Without severe OIEARR n (%)	With severe OIEARR n (%)	p-value
rs307247	AA	8 (11.9)	13 (14.3)	reference
	AG	31(46.3)	46 (50.5)	0.857
	GG	28 (41.8)	32 (35.2)	0.496
rs6256	TT	3 (4.5)	1 (1.1)	reference
	GT	22 (32.8)	21 (23.6)	0.360
	GG	42 (62.7)	67 (75.3)	0.143
rs694	CC	13 (19.1)	13 (14.3)	reference
	CT	28 (41.2)	49 (53.8)	0.219
	TT	27 (39.7)	29 (31.9)	0.880

The results of the binary logistic regression analysis are presented in Table 5. The multivariable model adjusted for sex and facial profile did not show statistically significant associations (p>0.05).

Table 5
Binary logistic regression analysis for severe OIEARR.

Variable / Category	B	S.E.	Wald	df	p-value	Exp (B) [OR]	95% CI for Exp(B)
rs694
Male vs. Female	-0.394	0.353	1.243	1	0.265	0.675	[0.338, 1.348]
Type of profile	—	—	0.612	2	0.736	—	—
Class II vs. Class I (Reference)	-0.396	0.515	0.593	1	0.441	0.673	[0.245, 1.844]
Class III vs. Class I (Reference)	-0.178	0.443	0.162	1	0.687	0.837	[0.351, 1.993]
rs694 (Overall)	—	—	3.066	2	0.216	—	—
CT vs. CC (Reference)	0.625	0.470	1.772	1	0.183	1.869	[0.744, 4.693]
TT vs. CC (Reference)	0.064	0.483	0.017	1	0.895	1.066	[0.414, 2.747]
rs6256
Male vs. Female	-0.296	0.352	0.705	1	0.401	0.744	[0.373, 1.484]
Type of profile	—	—	0.132	2	0.936	—	—
Class II vs. Class I (Reference)	-0.180	0.518	0.120	1	0.729	0.836	[0.303, 2.307]
Class III vs. Class I (Reference)	-0.139	0.446	0.097	1	0.756	0.870	[0.363, 2.087]
rs6256 (Overall)	—	—	3.383	2	0.184	—	—
GT vs. GG (Reference)	-0.503	0.365	1.898	1	0.168	0.605	[0.296, 1.237]
TT vs. GG (Reference)	-1.586	1.182	1.800	1	0.180	0.205	[0.020, 2.077]
rs307247
Male vs. Female	-0.352	0.352	1.000	1	0.317	0.703	[0.352, 1.403]
Type of profile	—	—	0.431	2	0.806	—	—
Class II vs. Class I (Reference)	-0.337	0.513	0.430	1	0.512	0.714	[0.261, 1.953]
Class III vs. Class I (Reference)	-0.201	0.440	0.208	1	0.648	0.818	[0.346, 1.937]
rs307247 (Overall)	—	—	1.009	2	0.604	—	—
AG vs. AA (Reference)	-0.019	0.517	0.001	1	0.970	0.981	[0.356, 2.705]
GG vs. AA (Reference)	-0.354	0.527	0.451	1	0.502	0.702	[0.250, 1.973]

• Note: Exp(B) represents the exponentiated logistic regression coefficient, corresponding to the odds ratio (OR). The 95% CI for Exp(B) indicates the 95% confidence interval for the odds ratio.

Discussion

OIEARR is recognized as a multifactorial phenomenon resulting from the interaction between biomechanical, biological, and genetic factors.⁴-⁶ Previous studies have shown that genetic polymorphisms in different genes, such as inflammatory-related genes (IL-1A, IL-1B, IL1RN, IL-6, and COX2),¹⁹-²⁴ genes involved in bone remodeling (OPG, RANK, and RANKL)²²,²⁵ and vitamin-related genes (VDR and CYP27B1)¹²,¹³ are associated with susceptibility to OIEARR after orthodontic treatment. However, to the best of our knowledge, this is the first study to investigate the association between genetic polymorphisms in PTH and OIEARR.

In this study, only the rs6256 polymorphism in the gene encoding PTH showed a borderline association with severe OIEARR in orthodontic patients indicated for orthognathic surgery. This finding reinforces the hypothesis that specific genetic polymorphisms can modulate tissue response to orthodontic forces, especially in clinical contexts involving greater biomechanical complexity, such as patients with malocclusion requiring orthognathic surgery. The higher frequency of the G allele of the rs6256 polymorphism in the severe OIEARR group suggests a possible role of this variant in OIEARR. However, both genotypic and multivariate analyses revealed no statistically significant association between PTH polymorphisms and OIEARR. Although a borderline association was detected in the allele distribution of rs6256, the lack of statistical significance in the broader models suggests that a true biological association may either be absent or represent a subtle effect detectable only in a substantially larger sample. Consequently, while PTH variation remains a relevant candidate, these findings highlight the need for larger, adequately powered samples to determine whether the observed trend for rs6256 reflects true biological susceptibility or stochastic variation.

It is well known that PTH is central in regulating bone metabolism, acting directly on osteoclastic activation and the balance between bone formation and resorption.⁸ PTH also plays a role in orthodontic tooth movement.²⁶ During orthodontic tooth movement, this balance is fundamental to physiological bone remodeling; dysregulation of this pathway may compromise the integrity of root structures. Studies using in vivo and in vitro approaches have concluded that intermittent PTH administration may promote cementoblast-mediated cementogenesis during periodontal repair and regeneration of dental roots affected by tooth resorption.¹⁰,²⁷Interestingly, under compressive conditions, periodontal ligament fibroblasts increase the expression of parathyroid hormone-related protein (PTHrP).²⁸

The rs6256 variant is located in exon 3 of the PTH gene and has been described as potentially associated with functional alterations in the protein, including the possibility of forming a premature stop codon.²⁹ It is possible that functionally altered PTH may favor increased osteoclastic activity in the periodontal ligament, thereby intensifying root resorption processes in response to the continuous mechanical stress imposed by orthodontic treatment, especially in patients requiring orthognathic surgery, who may undergo longer orthodontic treatment. The rs694 variant, located in an intronic region, and rs307247, located in a downstream region of the gene, may not be relevant to OIEARR. However, the rs694 variant was recently associated with increased mandibular bone fractal dimension.³⁰

Among the strengths of this study is the inclusion of a clinically homogeneous population composed exclusively of patients with severe skeletal malocclusion and an indication for orthognathic surgery. This characteristic reduces variability related to the biomechanical demands of treatment, enabling a more precise evaluation of the genetic influence on OIEARR. Conversely, some limitations should be considered. The sample size may have restricted the detection of associations with the polymorphisms if they have small effects on the phenotype.

Additionally, although PTH is a central regulator of bone metabolism, other genes and inflammatory mediators, including genes involved in bone remodeling and vitamin-related genes, have also been implicated in susceptibility to OIEARR and were not jointly analyzed in this study. Therefore, future investigations using multigenic models are necessary to fully elucidate the involved mechanisms.

In summary, the results of this study reinforce the multifactorial nature of OIEARR and its potential polygenic background. These findings contribute to the understanding of the biological basis of OIEARR and support the potential future application of genetic markers in individualized clinical planning and the prevention of severe iatrogenic complications in orthodontic practice.

Conclusion

The G allele of the rs6256 polymorphism showed a borderline association with severe OIEARR. The multivariable model adjusted for sex and facial profile did not show statistical associations between the studied PTH genetic polymorphisms and OIEARR. Our results suggest that the rs6256 polymorphism in the gene encoding PTH may be associated with severe OIEARR.

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Data availability statement:

All data generated or analyzed during this study are included in this published article

Correspondence:

Flares Baratto-Filho - Universidade da Região de Joinville (Univille) - Departamento de Odontologia - Joinville - Santa Catarina – Brasil - Email: [e-mail]

Editor:

Ana Carolina Magalhães

Associate Editor:

Felícia Miranda

Conflict of interest:

The authors declare no conflict of interest.

Publication Dates

• Publication in this collection
  06 Nov 2026
• Date of issue
  2026

History

• Received
  05 Aug 2026
• Reviewed
  18 Sept 2026
• Accepted
  27 Sept 2026