ORIGINAL RESEARCH |
https://doi.org/10.5005/jp-journals-10015-2040 |
Effect of Fluoride Agents on Calcium Metabolism of Patients Undergoing Orthodontic Treatment: A Randomized Trial
1Department of Orthodontics, Army College of Dental Sciences, Secunderabad, Telangana, India
2Department of Orthodontics, MS Ramaiah University of Applied Sciences, Bengaluru, Karnataka, India
3Department of Mechanical Engineering, MS Ramaiah University of Applied Sciences, Bengaluru, Karnataka, India
Corresponding Author: Prasad Chitra, Department of Orthodontics, Army College of Dental Sciences, Secunderabad, Telangana, India, Phone: +91 9849020018, e-mail: prasadchitra@yahoo.co.uk
ABSTRACT
Aim: To avoid enamel demineralization, orthodontists generally prescribe fluoridated agents to their patients. The effects of fluorides on underlying biological tissues are not well-known. Previously published literature on animal studies provides evidence of fluorides modifying calcium metabolism. This study analyzes the effects of fluoridated mouthwashes and toothpastes on calcium metabolism in orthodontic patients.
Materials and methods: A prospective randomized trial allocated 90 subjects to two treated groups (30 each), one group using nonfluoridated toothpaste and the other group using fluoridated toothpaste and mouthwashes and a control group with no intervention. All patients had uniform bracket prescriptions and were treated with similar archwire sequences. Blood samples at four specific time periods (before treatment,1 week, 30 days, and 6 months) were collected in a heparinized syringe and centrifuged to retrieve serum plasma. Serum thus collected was assessed for any alterations in calcium levels using a calcium test kit and comparisons of changes were made.
Results: Maximum decrease in serum calcium levels were noted at 7 days in both fluoridated and nonfluoridated groups, although the results were not statistically significant at p < 0.001.
Conclusion: The use of fluoride agents during fixed orthodontic therapy does not carry significant risk in alteration of calcium metabolism. However, known hypocalcemic patients can be given additional calcium supplements to avoid hypocalcemia. Additionally, this mild decrease in serum calcium could also favor the rate of orthodontic tooth movement. However, further studies are required in order to provide evidence for the same.
Clinical significance: Fluoride containing oral hygiene agents should be used with caution in patients with decreased calcium levels.
How to cite this article: Chitra P, Prashantha GS, Rao A. Effect of Fluoride Agents on Calcium Metabolism of Patients Undergoing Orthodontic Treatment: A Randomized Trial. World J Dent 2022;13(3):207-213.
Source of support: Nil
Conflict of interest: None
Keywords: Calcium metabolism, Fluoride, Tooth movement
INTRODUCTION
Calcium (Ca) is the human body’s fifth most abundant element and is essential for survival.1 The body stores most Ca (99%) in the form of hydroxyapatite in the skeleton which also serves to provide skeletal support. It also preserves the natural serum Ca level (8–10 mg/dL) by regulating various functions.2 A very nominal amount of Ca (1%) is found in soft tissues, skin, and extracellular fluid (ECF). Serum Ca is present either bound to protein (~40%), mainly albumin, bound in the form of a complex to anions (e.g., phosphate or citrate; ~9%) or free or ionized (~51%). The ionized form of Ca is available for cell entry and stimulates important physiological processes. The major hormone that controls absorption of intestinal Ca is 1,25-Dihydroxyvitamin D3 [1,25(OH)2D3], which is a hormonally active form of vitamin D.3 The parathyroid hormone (PTH) and ionized Ca also help regulate Ca homeostasis.4
In attaining Ca homeostasis, important roles are assayed by the kidneys, skeleton, and intestinal system. About 10 gm of Ca passes the kidneys daily with around 200 mg excreted through urine and the majority reabsorbed.5 However, the typical 24-hour excretion of Ca can range from 100–300 mg per day (2.5–7.5 mmol/day). The major Ca repository in the body is the skeleton. Around 500 mg of Ca is released and accreted daily through bone turnover.
Strong control of ECF Ca concentration is maintained by the activity of Ca sensitive cells modulating hormone synthesis.6 These hormones work on individual bone, stomach, and kidney cells that can react to preserve ECF Ca by modifying Ca fluxes.
PTH increases Ca reabsorption in the kidney and decreases phosphate reabsorption by generating phosphaturia at the same time. The conversion of the vitamin D 25-hydroxyvitamin D (25OHD) inert metabolite to the 1,25-dihydroxyvitamin D [1,25(OH)2D] active form occurs by PTH and hypocalcaemia itself.7 As a result, intestinal absorption of Ca increases along with renal phosphate reabsorption to a lesser extent by mobilizing Ca from bone, with increase in gut absorption of Ca to restore normal ECF Ca and disallowing production of PTH and 1,25(OH)2D by nephron filtration of Ca. In addition, the released FGF23 could reduce 1,25(OH)2D.8 PTH output also decreases, ensuring Ca homeostasis is restored. The opposite sequence of events happens when ECF Ca is increased above normal limits.5
Orthodontic tooth movement (OTM) and bone remodeling activity is dependent on systemic and external conditions such as nutritional factors, metabolic diseases, age, and use of drugs or hormones. During the early phase of OTM, an intense inflammatory reaction to mechanical force characterized by periodontal vasodilatation occurs. This initially induces fluid movement within the periodontal ligament space and destruction of periodontal ligament components (cells, extracellular matrix, and nerve terminals), allowing the release of a large number of molecules that activate alveolar bone remodeling (neurotransmitters, cytokines, growth factors, arachidonic acid metabolites, etc.).9 Many conditions involving Ca homeostasis that changes bone physiology are usually found in women, such as osteoporosis, which is counteracted by Ca and vitamin D supplements.10 Systemic conditions involving Ca disorders demonstrate variations in OTM rates. By operating at a molecular level—interfering with local target cells via circulation, these drugs, along with orthodontic forces, may cause synergistic or inhibitory effects on tooth movement. Low Ca levels are responsible for secondary hyperparathyroidism causing rise in secretion of PTH and active metabolites of vitamin D. PTH can induce rapid Ca release in the bone.11-13
Goldie et al. also observed that OTM was improved by systemic Ca deficiency.12 Research by Seifi et al. also showed that rate of OTM was significantly lower in the Ca group as compared to controls.14 Also, considering the vital role of PTH in controlling bone resorption, serum Ca level shifts could be decisive for root resorption.15 Thus, it seems possible that elevated serum Ca levels can inhibit the secretion of PTH and therefore inhibit the resorption of the root. The metabolism of Ca and phosphorus is directly linked to the development of osteoblasts and osteoclasts as well as their precursors, potentially contributing to a shift in the rate of OTM.
The correlation between serum levels of different elements such as Ca, magnesium, phosphorous, and fluoride is complex and is determined by numerous biological factors. Fluorine induces osteoblasts and triggers a rise in Ca deposition and increased bone density.16 This leads to the consideration that fluorine salts could be used to treat osteoporosis patients to cause an extent of osteosclerosis that would positively impact the skeleton. In 60 human subjects treated for up to 6 months with an average daily dosage of 320 mg sodium fluoride (NaF), equivalent to 2.4 mg fluoride per kg per day for 60 kg subjects, there was no evidence of toxicity.17 Others, however, have found this dosage amount to be harmful when given to humans or small mammals for extended periods of time.18
Thus, if fluoride is to be used in a clinical trial, it is important to monitor both the dosage and the length of therapy. Therefore, the aim of the study was to assess and quantify serum Ca levels of untreated controls and patients undergoing orthodontic treatment with and without exposure to fluorides.
MATERIALS AND METHODS
Trail Design
An open-ended randomized clinical trial design was adopted and utilized for selection of patients seeking orthodontic treatment. The study was reviewed and approved by the Institutional Ethical Committee. Prior to inclusion in the study, written informed consent was obtained from all participants. This study had a balanced allocation ratio of 1:1:1.
Sample Size
Sample size estimation was finalized using G Power software version 3.1.9.2 after performing a power analysis. Considering the effect size to be measured (f) at 40 %, power of the study at 80% and the margin of error at 5%, the total sample size needed was 66. The final sample size was rounded off to 75 to include 25 subjects in each group. An additional five subjects per group were included to consider dropouts, if any.
Eligibility Criteria and Formulating Research Protocol
Ninety subjects with following inclusion criteria: patients requiring nonextraction fixed orthodontic treatment between the ages of 12–35 years, all permanent teeth till 2nd molars to be present, no history of smoking or alcohol intake and no history of use of medications like antibiotics in the preceding 6 months and no Ca disorders comprised the sample which was further subdivided into Groups 1, 2, and 3 as: Group 1—30 untreated controls (not undergoing any form of treatment), Group 2—30 patients treated with fixed orthodontic appliances and using nonfluoridated toothpaste (Dabur Red, Dabur India Ltd), and Group 3—30 patients treated with fixed orthodontic appliances and using fluoridated mouthwashes and toothpaste (Colgate Plax, 225 ppm fluoride, Colgate Strong Teeth, 1000 ppm fluoride, Colgate Palmolive Co, India). All treatment procedures were carried out in a single setting under the direct supervision of one author.
Intervention
Group 2 and 3 patients had fixed orthodontic appliances with a defined sequence of archwires during the six-month period in order to make comparisons between groups. An equal number of untreated controls were also included for assessment and comparisons. Fixed orthodontic appliances were bonded in all patients in both arches simultaneously. Stainless steel brackets (Mini Twin 0.022 slot, Ormco Corporation, Glendora, CA) were bonded using light cured adhesive (Enlight, Ormco Corporation, Glendora, CA). The archwires used in the study were nickel titanium (NiTi) 0.014,” 0.016” and 16 × 22” till 6 months of treatment.
The untreated control group and Group 2 subjects were instructed to use nonfluoridated toothpaste twice daily for maintaining hygiene. Also, Group 3 subjects were instructed to use a fluoridated mouthwash and toothpaste twice daily.
Randomization
Simple randomization using a computer-generated random number (https://www.graphpad.com/quickcalcs) at the beginning of the study for allocation of the mouthwash to the participants was done.
Blinding
Both the patients and the investigators were blinded to the allocation of the mouthwash as it was provided in a clear bottle to the patients at the time of placement of archwire. The investigators were also blinded for measurements by assigning each patient’s test tube a number to innominate the data.
Data Collection
After obtaining prior written consent from all participants, blood samples were collected before the start of treatment (baseline), at 1 week, 30 days, and 6 months from all three groups. Measurement of blood Ca levels were done according to previously published studies.16,19 Blood samples from subjects were drawn using a heparinized syringe, placed into a 1.5 mL tube and centrifuged for 3 minutes at 15,000 rpm. Post centrifugation, the separated plasma was frozen at −20°C till analysis. A Beacon Ca test kit analyzed total Ca levels (mg/100 mL) in plasma. The test kit consisted of three reagents as follows: Reagent 1 [Ca (O-cresolphthalein complexone) reagent], reagent 2 (Diethanolamine buffer), and reagent 3 (Ca standard 10 mg/dL). All the reagents were first brought to room temperature. The working reagent was prepared by mixing equal parts of reagents 1 and 2 in a 1:1 ratio.
The working reagent was then pipetted into test tubes which were completely dry and clean labelled as “Blank,” “Standard,” and “Test.” All the patient’s serum samples were placed in “Test” tubes. Reagent 3 was added to “Standard” tube. The addition sequence has been described in Table 1. The entire contents were mixed well and incubated for 5 minutes at room temperature. The absorbance of the Standard (Abs.S) and Test (Abs.T) against the reagent blank at 578 nm (530–590 nm) was measured within 15 minutes.
| Addition sequence | Blank | Standard | Test |
|---|---|---|---|
| Working reagent | 1.0 mL | 1.0 mL | 1.0 mL |
| Standard | – | 20 µL | – |
| Sample | – | – | 20 µL |
mL, milliliter; µL, microliter
Measurement
Serum Ca levels were calculated as follows:
Calcium concentration (mg/dL) = Abs.T/ Abs.S × 10
The normal value of serum Ca level is 9.0–10.6 mg/dL. Any values greater or less than this range were considered as hypercalcemia or hypocalcemia, respectively.
Statistical Analysis
Statistical Package for Social Sciences (Ver22.0 Released 2013. Armonk, NY: IBM Corp) was utilized for statistical analyses. Descriptive analysis included alteration of mean and standard deviation Ca levels for each group. One-way ANOVA test followed by Bonferroni post hoc analysis was utilized to compare Ca levels at each interval among three study groups. Two-way ANOVA was done to compare Ca levels and their treatment*time interactions. Repeated measures of ANOVA followed by Bonferroni post hoc test was used to compare Ca levels across different time intervals within each group. The level of significance was set at p < 0.05.
RESULTS
The demographic representation of study subjects is given in Flowchart 1. Results of the present study are discussed under the following headings:
-
Assessment of change in calcium levels across different time intervals within each group
-
Assessment of calcium levels at each interval among three study groups
-
Comparison of change in calcium levels among three study groups
-
Two-way ANOVA results comparing calcium level values.
Flowchart 1: CONSORT diagram of demographic representation
Assessment of Change in Calcium Level Across Different Time Intervals Within Each Group
Repeated measures of ANOVA test was performed to assess the change in Ca levels across different time intervals for all three groups. Serum levels showed a statistically significant decrease over a 6-month period. The maximum decrease was noted at 7 days with increase in Ca levels till 6 months in both fluoridated and nonfluoridated groups as noted in Table 2 (p < 0.001).
| Groups | Baseline | 7 days | 30 days | 6 months | p-value |
|---|---|---|---|---|---|
| Control | 9.80 (0.41) | 9.81 (0.41) | 9.82 (0.43) | 9.79 (0.41) | 0.078 |
| Nonfluoride | 9.81 (0.37) | 9.59 (0.46) | 9.67 (0.38) | 9.76 (0.38) | 0.001* |
| Fluoride | 9.79 (0.37) | 9.56 (0.53) | 9.64 (0.44) | 9.74 (0.38) | 0.001* |
*Statistically significant
On evaluating pair wise Ca level changes across multiple time intervals using post hoc Bonferroni test, Ca levels in both Group 2 nonfluoridated and Group 3 fluoridated subjects showed statistically significant decrease at 7 days, 30 days, and 6 months when compared to the control group at all intervals at p < 0.05. This infers that there was no difference between both fluoridated and nonfluoridated groups (Table 3).
| Groups | B vs 7 | B vs 30 | B vs 180 |
|---|---|---|---|
| Control | 1.000 | 1.000 | 0.804 |
| Nonfluoride | 0.003* | 0.001* | 0.002* |
| Fluoride | 0.002* | 0.001* | 0.040* |
*Statistically significant
Assessment of Calcium Levels at Each Interval among Three Study Groups
On comparing mean Ca levels at each interval among three groups using One-way ANOVA, a marked decrease in serum Ca levels was noted over a period of 7 days in both Groups 2 and 3, which did not show statistical significance at p < 0.001. This value later increased from a period of 30 days to 6 months at p > 0.001 (Table 4). There was no change in baseline over the entire duration.
| Groups | Control | Nonfluoride | Fluoride | p-value |
|---|---|---|---|---|
| Baseline | 9.80 (0.41) | 9.81 (0.37) | 9.79 (0.37) | 0.986 |
| 7 days | 9.81 (0.41) | 9.59 (0.46) | 9.56 (0.53) | 0.090 |
| 30 days | 9.82 (0.43) | 9.67 (0.38) | 9.64 (0.44) | 0.194 |
| 6 months | 9.79 (0.41) | 9.76 (0.38) | 0.74 (0.38) | 0.910 |
Group 1 subjects showed no significant changes in serum Ca levels. In Group 2, a mean decrease of 0.22 mg/dL was noted at 7 days which further increased by 0.08 mg/dL with a final mean decrease from baseline to 6 months at 0.05 mg/dL. In Group 3, a mean decrease of 0.23 mg/dL was noted at 7 days which increased by 0.08 mg/dL with a final mean decrease from baseline to 6 months was 0.05 mg/dL. However, a marked decrease was noted at 7 days for both groups which was not statistically significant (Fig. 1A). Pairwise comparison of Ca levels at each interval among three study groups using post hoc Bonferroni test suggested a decrease in the serum Ca levels over a period of 6 months with maximum decrease at 7 days at p > 0.001.
Figs 1A and B: (A) Calcium levels among three groups at each interval; (B) Change in calcium level among three study groups
Comparison of Change in Calcium Level among Three Study Groups
The mean change in Ca levels among all three groups was assessed using One-way ANOVA test. At 1 week, the difference between Group 2 to baseline was 0.22 and Group 3 to baseline was 0.23 at p < 0.001. At 30 days, the difference between Group 2 to baseline was 0.14 and Group 3 to baseline was 0. 15 at p < 0.001. At 6 months, the difference between Group 2 to baseline was 0.05 and Group 3 to baseline was 0.05 at p > 0.001 (Table 5 and Fig. 1B).
| Groups | Control | Nonfluoride | Fluoride | p-value |
|---|---|---|---|---|
| B vs 7 | −0.01 | 0.22 | 0.23 | 0.001* |
| B vs 30 | −0.02 | 0.14 | 0.15 | 0.001* |
| B vs 180 | 0.01 | 0.05 | 0.05 | 0.146 |
*Statistically significant
Two-way ANOVA Results for Comparison of Calcium Level Values
On assessing the interaction between treatment and time for comparison of Ca levels among three groups using Two-way ANOVA, serum Ca levels showed significant decreases over the entire treatment duration in both Groups 2 and 3 at p < 0.001. This shows that the effect of interaction of time and treatment on Ca levels was significant (Table 6).
| Type III sum of squares | df | Man squares | F | p-value | |
|---|---|---|---|---|---|
| Treatment | 0.991 | 2 | 0.495 | 5.138 | 0.009* |
| Error | 5.592 | 58 | 0.096 | ||
| Time | 1.158 | 3 | 0.386 | 11.458 | 0.001* |
| Error | 2.930 | 87 | 0.034 | ||
| Treatment*Time | 0.716 | 6 | 0.119 | 10.514 | 0.001* |
| Error | 1.974 | 174 | 0.011 |
*Statistically significant
DISCUSSION
Hypocalcemia is the diagnostic term for an electrolyte deficit that occurs in the blood due to less than 9 mg/dL of Ca. This condition may lead to injury to muscles and in extreme circumstances, could also interfere with the operation of the heart and brain. Ca levels that are too low can also contribute to osteoporosis, weak muscles, and osteopenia, a precursor of osteoporosis. Parathyroid gland dysfunction and lack of vitamin D are usually causative factors. However, some local interferences with increased exposure to fluoridated compounds also act as contributing factors. The body uses Ca from the teeth and bone once Ca levels in the body drop, leading to tooth decay or tooth loss. Osteoporosis is one of the major diseases arising from a long-term Ca deficiency that affects not just the bones, but also the teeth. It may result in formation of hypomineralized teeth or weaken jaw bones which in turn may cause increased periodontal problems.20 At the molecular level, mediators such as OPG and RANKL are essential for the stimulation or inhibition of osteoclastogenesis by various systemic hormones. Ca causes a negative osteoclast differential in osteoblasts through inhibiting RANKL and increasing the positive signal, OPG. It has been proposed that a precise equilibrium between the production of RANKL and the inhibition of OPG is needed to initiate or accelerate hormonally controlled tooth movement or bone turnover.21
A common concern that marks the result of a successfully completed orthodontic case is enamel demineralization around fixed orthodontic attachments.22 Orthodontists recommend using cariostatic agents such as fluoridated toothpastes and mouthwashes as fluoride improves remineralization of enamel.23-25 The cariostatic effect of fluorides is primarily attributed to Ca fluoride deposition.26 Biosafety is a valid concern as these products are used for relatively long time periods intraorally.
Gradual degradation of dental products used in the mouth enables the introduction of metal ions into the mouth, impacting their mechanical properties.27 Many experiments28,29 have been performed to determine the influence of the release of metal ions from brackets and archwires. There are, however, relatively few studies evaluating the effect of fluoridated agents in vivo. The biological effects of fluorides at a hematological level were evaluated in this study.
In the present study, serum Ca levels were recorded in 90 subjects in three groups using nonfluoridated and fluoridated oral hygiene products. About 0.05% NaF mouthwash in conjunction with fluoridated toothpaste (1000 ppm) was given to Group 3 patients for daily use for a period of 6 months. Similar changes in serum Ca levels were observed in both Group 2 [nonfluoridated] as well as Group 3 [fluoridated] subjects indicating that there was no evidence of fluoride agents exerting any effects on serum Ca levels.
In order to validate the effect of fluorides on Ca metabolism, serum Ca levels were assessed in this study with a decrease in serum Ca levels noted in both nonfluoridated and fluoridated groups as compared to baseline groups. It was noticed that the maximum decrease was noted in both groups at 7 days with a mean decrease in serum Ca level from 9.81–9.76 mg/dL in Group 2 and from 9.79–9.74 mg/dL in Group 3. Although, serum Ca levels decreased, their level was still under the normal serum Ca range suggesting no harmful effects on use of fluoridated oral hygiene products in patients undergoing fixed orthodontic therapy. The mean serum Ca levels decreased from baseline to the 7-day period (0.23), which later increased over a period of 6 months. Amongst all three groups, maximum decrease was with use of fluoridated mouthwashes at 7 weeks, during the clinical treatment phase, although the results were not statistically significant. However, in pairwise comparison of Ca levels at each interval among three study groups suggested a decrease in the serum Ca levels over a period of 6 months with maximum decrease at 7 days at p > 0.001. When compared with the nonfluoridated group, there was not much change in the Ca levels at 30 days, and it remained stable over a period of 6 months (mean decrease from baseline– 0.05 mg/dL). No damaging effects were observed with the use of fluoridated toothpaste and mouthwash.
Many animal experiments have found alterations in Ca metabolism with fluoride treatment. Extrapolation of this evidence on human subjects has not, however, been contemplated. The study revealed a drop in serum Ca levels over a span of 6 months in both the fluoridated and nonfluoridated groups, but this was not statistically important.
Fluorapatite is a poorly soluble form of Ca that causes hypocalcemia.30 Ca inhibits fluoride removal from the gastrointestinal tract. Therefore, if Ca supplements are given along with NaF, it is possible to fight the hypocalcemic condition.
Chinoy et al. in his study found no depletion of locomotor behavior or any other parameters in animals treated with Ca supplements and NaF.31 This highlights the fact that Ca supplements help reduce the body’s fluoride load, thus counteracting the body’s excess fluoride toxicity. The results are similar to that obtained by others who documented excessive fluoride exposure to alteration in Ca metabolism in patients.16,19,30 It can be suggested that although there were no harmful effects observed on use of fluoridated toothpaste and mouthwash during the course of routine fixed orthodontic therapy, Ca supplementation in patients with Ca deficiency receiving orthodontic treatment could also help.
Rate of OTM is closely interrelated to serum Ca levels. Kanzaki et al. found that calcitonin had a direct stimulatory impact on bone formation and osteoblast mineralization.32 Four studies evaluated the effect of Ca or calcitonin on OTM.12,14,33,34 They showed a substantial reduction in OTM, which was statistically significant. It was noticed that by minimizing the number of osteoclasts at the root and alveolar bone at the pressure site, various doses of calcitonin exhibited inhibition of OTM.33 Hence, exposure to fluoridated oral hygiene products could also have an indirect effect of accelerating OTM by altering serum Ca levels. This statement however, requires further investigation prior to confirming.
CONCLUSION
The study has provided evidence that fluoridated toothpastes and mouthwashes do not alter Ca metabolism in patients undergoing fixed orthodontic treatment. The Ca levels decreased at the 7-day observation period in both Group 2 [nonfluoridated] and Group 3 [ fluoridated] subjects, though not at statistically significant levels. This decrease in Ca level could also accelerate OTM. It should, however, be held in mind that in real in vivo environments, multiple factors are responsible for ultimate results. Saliva type and pH, diet, bone thickness and quality, general health and subject actions may all serve as confounding variables for final outcomes. In cases where patients have Ca disorders or lack of Vitamin D, additional Ca supplements could reduce hypocalcemia risks.
CLINICAL SIGNIFICANCE
It is necessary for clinicians to recognize patients with Ca metabolism disorders on various types of medications prior to beginning orthodontic treatment. Though systemic ingestion of fluorides through oral hygiene agents is very low, caution should be exercised in patients on Ca supplements during orthodontic treatment by recommending use of nonfluoridated oral hygiene agents for the duration of therapy.
ORCID
Prasad Chitra https://orcid.org/0000-0002-7371-0738
GS Prashantha https://orcid.org/0000-0003-2733-0459
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