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

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.


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.

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?".

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, interexaminer 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.

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.

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.

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.

General Characteristics and Outcomes of Studies
The general characteristics are given in Table 1.

General Characteristics and Outcomes of Studies
The general characteristics are given in Table 1. In two studies (by Soma et al. 2000 andLi 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].

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.

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. Data Availability Statement: Study data is available from the corresponding author on request.