Influence of Intermittent Parathyroid Hormone (PTH) Administration on the Outcomes of Orthodontic Tooth Movement—A Systematic Review

Abstract

Objective: The aim of this review is to summarize the effects of local and systemic PTH administration on periodontal tissues during orthodontic tooth movement. Materials and methods: An electronic search was conducted on the following databases: PubMed/MEDLINE, Google Scholar, SCOPUS and Embase. On PubMed/MEDLINE, the Medical Subject Headings (MeSH) keywords used were: “orthodontic tooth movement” OR (“tooth” (All Fields) AND “tooth movement” (All Fields)) OR “tooth movement” (All Fields)) AND (“parathyroid hormone”); all studies included using CONSORT. Results: After elimination of duplicates and articles not meeting our inclusion criteria, seven animal studies were included in this review. Although the majority of the studies suggest that PTH may a have a favorable outcome on OTM, most studies were found to have several sources of bias. Conclusion: Animal studies with minimal bias and long-term clinical studies are needed to ascertain the efficacy of intermittent PTH administration in improving the rate and retention of OTM.

1. Introduction

Orthodontic treatment involves the movement of teeth by application of forces via removal and fixed appliances [1]. Orthodontic tooth movement (OTM) is the result of bone resorption on the pressure side and bone apposition on the tension side [2]. To put it simply, OTM is made possible by a combination of bone formation and resorption [3]. A number of factors can affect the rate of OTM. These include systemic disease such as diabetes [4], osteoporosis [5] and other metabolic disorders. Drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) and bisphosphonates [6] have also been observed to affect the rate of OTM. Furthermore, oral diseases such as periodontitis also adversely affect the outcome of orthodontic treatment [7]. To improve the rate of OTM and reduce the probability of orthodontic relapse, a number of methods have been proposed. These include surgery, transeptal fiberectomy and low-level laser therapy [8,9]. However, surgery is traumatic and procedures such as laser therapy have limited efficacy. Moreover, rapid OTM may cause root resorption. Additionally, periodontitis can exacerbate the root and bone resorption induced by OTM [10].

More recently, local and systemic application of drugs and hormones has been suggested to improve the rate of OTM [11]. Parathyroid hormone (PTH) is a hormone that is produced and secreted by the parathyroid gland. Its primary function is to regulate the serum calcium concentration by exerting its effect on bone, kidney and the intestine [12]. Its synthetic (in the form of teriparatide) and recombinant forms are used in the treatment of parathyroid deficiency and osteoporosis [13]. Unsurprisingly, the effect of PTH on periodontal tissues during OTM has also been studied [14]. It has been observed that low doses of intermittent PTH (in local or systemic forms) may accelerate OTM, reduce the probability of relapse [15] and may reduce alveolar bone resorption caused by periodontitis during OTM [16]. However, to date, no extensive systematic review has been published that comprehensively assesses the overall quality of the studies and summarizes their general outcomes. Hence, the aim of this systematic review is to assess the quality of literature and summarize the overall effects of local and systemic administration of PTH on OTM.

2. Materials and Methods

2.1. Focused Question

Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the Participants, Intervention, Control and Outcomes statement (PICO) [17], the following focused question was formulated: “What is the effect of local and systemic parathyroid hormone on outcomes of orthodontic tooth movement when compared to orthodontic force alone?”.

2.2. Search Methodology

Between November 2020 and February 2021, an electronic search was conducted on the following databases: PubMed/MEDLINE, Google Scholar, SCOPUS and Embase. On PubMed/MEDLINE, the Medical Subject Headings (MeSH) keywords used were: “orthodontic tooth movement” OR (“tooth”(All Fields) AND “tooth movement” (All Fields)) OR “tooth movement”(All Fields)) AND (“parathyroid hormone” OR “teriparatide”(All Fields) OR “orthodontic”(All Fields)). Suitable filters were applied on the other database search engines to use the keywords: “orthodontic tooth movement” AND “parathyroid hormone” OR “teriparatide”. On Google Scholar and Embase databases, the relevant filters were applied to exclude articles not relevant to our study. Prior to our search, inter-examiner calibration and piloting exercises were carried out to reduce bias and improve inter-examiner reliability.

The inclusion criteria included randomized clinical trials, case series, case reports and animal studies, as well as dissertations on topics meeting our focused question. Letters to the editor, in vitro studies, ongoing trials, conference proceedings, reviews and commentaries were excluded. Articles published on and after the year 2000 were searched for. The language of the articles search was English. Reference lists of the studies found were also searched for any articles matching our inclusion criteria. The search was a conducted independently by the author and another investigator. Both were blinded to each other’s research results. Any disagreements were solved by discussion. Following the completion of the search, the general characteristics, outcomes, and overall quality of the articles were summarized and assessed by the investigators. The grey literature was searched with the assistance of the library services at College of Dentistry, King Faisal University (KFU), KSA. The outcomes of studies were assessed in terms of the effect of PTH administration on the rate orthodontic tooth movement, periodontal tissues, orthodontic relapse and root and/or bone resorption.

2.3. Grading of Studies

Using a modified scale derived from Consolidated Standards of Reporting Trials (CONSORT) [18], each of the studies included were graded. The following qualities of the studies were assessed: pre-determined sample size, blinding, randomization, appropriate statistics, reporting of any animals lost to the study and error analysis to assign each study a score of low, medium or high with low score having lowest overall quality and a high score having the highest overall quality. Any disagreements were solved by discussion.

3. Results

3.1. Search Results

Pubmed and Embase resulted in 25 and 27 hits, while Google Scholar resulted in excess of 2500 articles (see Figure 1). After exclusion of non-relevant articles, the primary search resulted in 51 articles when aforementioned databases were used for the search. The kappa score of inter-rater reliability was 0.85. After removal of duplicates, titles and abstracts of 23 articles were analyzed. Of these articles, 17 articles did not meet our research criteria. Hence, seven studies were included in this study [15,16,19,20,21,22,23]. All studies were animal studies with Wistar rats being the primary study model [15,16,19,20,21,22,23]. Of the 17 excluded studies, seven studies were in vitro studies, three studies were reviews and seven studies mentioned interventions not related to PTH in any way.

3.2. General Characteristics and Outcomes of Studies

The general characteristics are given in

Table 1. General characteristics and outcomes of studies included in this review. PTH: parathyroid hormone; OTM: orthodontic tooth movement; PD: periodontal disease.

Study	Animal Model (n)	Study Groups (n)	Duration and Methodology	Orthodontic Appliance; Force and Magnitude	Orthodontic and Periodontal Outcomes
Soma et al. 2000 [13]	Male Wistar rats (56)	Group 1 (8): OTM only Group 2 (8): OTM + vehicle in MC gel Group 3 (8): OTM + local 2% w/v PTH in 0.1 µg MC gel Group 4 (8): OTM + local 2% w/v PTH in 1 µg MC gel Group 5 (8): OTM + local 2% w/v PTH in 1 µg 0.9% saline Group 6 (8): OTM + systematic 2% w/v PTH in 1 µg MC gel Group 7 (8): Local 2% w/v PTH in 1 µg MC gel (no OTM)	12 days; bi-weekly injections of PTH	Coil spring; 30 g	PTH accelerated OTM. Local 2% w/v PTH in 1 µg MC gel had the highest impact on OTM.
Lossdörfer et al. 2010 [20]	Male Wistar rats (70)	Group 1 (35): 5 μg/kg PTH subcutaneous Group 2 (35): 5 μg/kg placebo	70 days; OTM applied until day 5. PTH injected from day 5 to 70 every other day; animals sacrificed on days 8, 10, 14, 17, 21, 56, and 70 for histological studies.	Not stated	PTH promoted higher periodontal repair post OTM compared to control.
Salazar et al. 2011 [21]	Female Wistar rats (48)	Group 1 (osteoporotic rats via ovariectomy) (16): OTM only Group: 2 (osteoporotic) (16): OTM + 30 µg/kg/day of teriparatide Group 3 (normal rats) (16): OTM only	7 days; OTM applied from day 1 until end of experiment. Histological assessment carried out at days 5 and 7.	Coil springs 40 cN	No significant difference in OTM and osteoclast activity between groups 1 and 2. Group 1 and 2 had faster OTM due to reduced bone density
Li et al. 2013 [19]	Male Wistar (60)	Group 1 (30): systemic 4 μg per 100 g, (1 µg/mL) PTH in PBS Group 2(30): PBS only	12 days; OTM applied from day 1 to 12. Six animals from each group killed on days 3, 6, 9, and 12 for histological studies	Coil springs; 40 g	PTH accelerated OTM by promoting remodeling of alveolar bone compared to control.
Lee et al. 2018 [15]	Female Sprague Dawley rats (30); 10 normal rats, 20 osteoporotic rats (via ovariectomy)	Group 1: Normal rats (10) Group 2 (osteoporotic): local placebo + OTM Group 3: local synthetic PTH + OTM	6 weeks; OTM applied from day 1. PTH/placebo injections 3 times per week. Coil removed after week 3 to study relapse	Coil springs; 30 g	No statistically significant effect of PTH on relapse in any group.
Zhang et al. 2020 [16]	Male Wistar rats (120)	Group 1 (60): Normal (20); PD (20); (PD + OTM) Group 2 (60): OTM + PD (15); OTM + PD with systemic PTH (15); OTM + PD + systemic PTH (15); OTM + PD + PTH + Stattic (15)	14 days total duration; PD induced by ligature wires; animals sacrificed on days 7 and 14 for histological examination; PTH concentration: 40 µg/kg	Coil spring (force not stated)	Systemic intermittent PTH might reduce alveolar bone loss during OTM in rats with periodontitis through STAT3/ β-catenin interaction.
Li et al. 2021 [22]	Male Wistar rats (48)	Group 1 (24): PTH in acetic acid vehicle + OTM Group 2 (24): Vehicle (acetic acid) + OTM	6 weeks duration; OTM for 4 weeks (2 weeks coil spring followed by 2 weeks of fixed wires); 2 weeks of no OTM to study relapse. 6 animals from each group sacrificed at weeks 0, 2 and 4.	Coil springs; 40 g	PTH reduced relapse after removal of orthodontic appliances compared to control groups.

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In two studies (by Soma et al. 2000 and Li et al. 2013) [19,23], local and systemic PTH accelerated OTM. In the study by Lossdörfer et al., PTH was observed to induce a higher amount of periodontal repair [20]. In the studies by Salazar et al. and Lee et al., PTH did not have any significant impact on PTM or periodontal tissues [21]. Zhang et al. observed that systemic intermittent PTH might reduce alveolar bone loss during OTM in rats with periodontitis through STAT3/β-catenin interaction [16]. Finally, in the 2021 study by Li et al., PTH reduced relapse after removal of orthodontic appliances compared to control groups [22].

3.3. Results of Quality Assessment

None of the studies used a predetermined sample size [15,16,19,20,21,22,23]. Four studies used randomization to allocate animals in their respective groups [15,16,19,22]. All studies used appropriate measurements and statistics [15,16,19,20,21,22,23]. Three studies did not use blinding [20,21,23]. None of the studies reported any loss (or no loss) of animals during the experiments [15,16,19,20,21,22,23]. Only one study involved error analysis [15]. Overall, two studies [15,19] were assessed to be of medium quality [15,19]. On the other hand, the remaining five studies were assessed to have a low quality [16,20,21,22,23]. The results of the quality assessment are provided in

Table 2. Results of the quality assessment.

Study	Pre-Determined Sample Size	Randomization	Appropriate Measurements	Statistics	Blinding	Loss of Animals Reported If Any	Error Analysis	Overall Quality
Soma et al. 2000 [23]	No	No	Yes	Yes	No	No	No	Low
Lossdörfer et al. 2010 [20]	No	No	Yes	Yes	Yes	No	No	Low
Salazar et al. 2011 [21]	No	No	Yes	Yes	No	No	No	Low
Li et al. 2013 [19]	No	Yes	Yes	Yes	Yes	No	No	Medium
Lee et al. 2018 [15]	No	Yes	Yes	Yes	No	No	Yes	Medium
Zhang et al. 2020 [16]	No	Yes	Yes	Yes	No	No	No	Low
Li et al. 2021 [22]	No	Yes	Yes	Yes	No	No	No	Low

. Quantitative assessment (meta-analysis) was not carried due to the heterogenicity of the outcomes and methodology among the studies, and a lack of standardized quantitative evaluation of the orthodontic outcomes.

4. Discussion

PTH plays a major role in maintaining the serum calcium concentration [12]. If the blood calcium levels get too low, PTH stimulates resorption of bone. PTH stimulates this resorption of bone by inducing a higher activity of osteoclasts, cells that are responsible for resorbing bone [24]. Hyperparathyroidism, a condition characterized by excessive levels of PTH in the blood, causes generalized loss of lamina dura in the periodontium and bone loss elsewhere in the body [25]. However, more recently, it has been observed that low intermittent doses of PTH actually promote bone formation [26]. Hence, low doses of intermitted PTH have been proposed for diseases such as osteoporosis [27].

The general outcomes of the studies included in this systematic review suggest that low doses of intermittent PTH may, to some extent, may have a favorable impact on alveolar bone, OTM and orthodontic retention [15,16,19,20,21,22,23]. However, to date, it is not clear how the hormone exerts all of those effects. Soma et al. have observed that PTH increases osteoclastic activity to increase bone resorption mainly on the compression side to accelerate OTM [23]. Lossdörfer et al. suggest that PTH induces a more rapid OTM via affecting the OPG/RANKL ratio [20]. They actually observed more pronounced changes in the OPG/RANKL ratio more during the late phases of OTM when compared to the earlier phases. Interestingly, they only detected an upregulation of OPG which may account for a reduced activity of osteoclasts and odontoblasts. Moreover, Zhang et al. observed that Systemic intermittent PTH might reduce alveolar bone loss during OTM in rats with periodontitis through STAT3/β-catenin interaction [16]. Nevertheless, it is evident that the exact mechanism of local or systemic administration of PTH has yet to be determined and more studies are needed to ascertain how PTH may influence the outcomes of OTM. In the studies reviewed, no distinct difference was observed between the efficacy of local or systemic PTH administration. As a matter of fact, only one study [13] looked at the differences between the effects of local and systemic PTH on OTM. Nevertheless, since systemic PTH may have undesirable adverse effects on the patient, it would be interesting to see how the local PTH administration compares with systemic injections of the hormones.

To date, no clinical studies have been carried to observe the effect of PTH on the alveolar bone loss, retention, and rate of tooth movement in patients undergoing OTM. Additionally, even in the animal studies reviewed in this paper, only one study observed the effect of PTH on OTM with periodontitis [16]. Therefore, future animal studies should also focus on observing the efficacy of PTH on OTM along with periodontal disease because it has been established that periodontal disease worsens the bone loss around teeth undergoing orthodontic treatment. The results of the quality assessment reveal that most studies possessed a high amount of bias. Only four studies mentioned some form of randomization [15,16,19,22] and only one study blinded the investigators [19]. Lack of blinding and randomization are major sources of biases results and make the evidence presented by the studies less reliable. Additionally, no study used a predetermined sample size which may have resulted in an insufficient sample size and lower level of evidence [15,16,19,20,21,22,23]. Moreover, no study mentioned if any animals were lost over the course of the experiments—an indicator of safety or adverse effects of regular PTH use [15,16,19,20,21,22,23]. In the future, studies with minimal sources of bias should be planned to provide a more conclusive evidence of efficacy of PTH in promoting OTM and reducing bone loss.

It is worthwhile to note that, to date, no clinical studies or trials have been carried out to ascertain LA the efficacy of PTH in accelerating OTM, preventing relapse or promoting bone formation and preventing bone loss around teeth affected by periodontitis undergoing OTM. Hence, future work should strive to contain human subjects in clinical trials with adequate follow up to ascertain the efficacy of PTH in accelerating OTM.

5. Conclusions

Current evidence suggests that low dose intermittent PTH may have a positive effect on the rate of OTM, alveolar bone and prevention of relapse following OTM. However, the animal studies included in this study have a variable quality. Moreover, long-term clinical studies with minimal bias are needed to ascertain the clinical efficacy and safety of PTH in contemporary orthodontics. Future animal studies should focus on adding blinding and randomization to minimize the bias. Additionally, since no clinical studies have been conducted to test the efficacy of PTH on OTM, clinical trials are required to ascertain the clinical efficacy of PTH in the clinical environment.