ISSN 2413-6077. IJMMR 2021 Vol. 7 Issue 266 D e n t is t r y DOI 10.11603/ijmmr.2413-6077.2021.2.12426 BONE TISSUE METABOLISM AND CHANGES IN THE ORAL CAVITY IN REDUCED FUNCTIONAL ACTIVITY OF THE THYROID GLAND (literature review) *О.V. Skochylo, S.I. Boitsanyuk, N.O. Tverdokhlib I. HORBACHEVSKY TERNOPIL NATIONAL MEDICAL UNIVERSITY, TERNOPIL, UKRAINE Background. Decreased functional activity of the thyroid gland leaves affects many organs and systems as well as bone tissue, pathological changes of which in the oral cavity are most often observed in periodontitis. However, the relationship between thyroid hypofunction and periodontitis or other inflammatory diseases of the oral cavity is still not confirmed. Objective. The aim of the review was to study the published information and analyse bone metabolism and its relationships between autoimmune thyroiditis and oral diseases. Methods. The articles in foreign periodicals on endocrinology, pathophysiology, dental surgery and therapy were the scientific sources for research. Results. Understanding the mechanisms of bone metabolism under the action of thyroid hormones is an important aspect of treatment and diagnostic process, as local treatment of dental pathology without reducing the impact on systemic factors ultimately does not have any positive result. Decreased functional activity of the thyroid gland leads to homeostasis imbalance in the body. The thyroid hormones are important for bone metabolism, publications on periodontitis incidence in cases of autoimmune pathology of the thyroid gland are the most common. However, despite the number of studies, most authors agree that they are currently insufficient to clearly establish a causal relationship between autoimmune thyroid disease and maxillofacial disorders. Conclusions. The study expands our knowledge, but there is still a need for further detailed studies that would clearly define the mechanisms of development of the disorders of the oral bone tissues and its relationships with autoimmune pathology of the thyroid gland. KEYWORDS: periodontitis; thyroid gland. *Corresponding author: Olha Skochylo, Department of Dental Surgery, I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine. E-mail: skochyloov@tdmu.edu.ua International Journal of Medicine and Medical Research 2021, Volume 7, Issue 2, p. 66-75 copyright © 2021, TNMU, All Rights Reserved Introduction Increased attention to the diseases of the thyroid gland is caused by challenging statistics on the increase in its incidence according to the Ministry of Health of Ukraine [1]. This trend is traced in the recent studies [2], their results show that the incidence of thyroid pathology has increased and is 46% of the total endo- crinological morbidity. According to the author, during the last 5 years in the western region of Ukraine the incidence of hypothyroidism increased by 28.4%, the increase of thyrotoxico- sis – by 8%, and the prevalence of thyroiditis – by 12.7% [2]. These indicators are higher than the national average indicators and that of the north-eastern regions. According to official WHO data, about 1.5 billion people suffer from thyroid disease at present. However, despite the effective treat- ment of endocrine pathology, the tendency to its reduce in the world is not observed [3]. Review Hypothyroidism, as the most common pathology of the thyroid gland, surely affects the functions and morphology of all tissues and organs, the maxillofacial area as well. It is established that insufficient thyroid hormones adversely affect both tooth mineralization, bone mineral density and calcium-phosphorus metabolism that is clinically observed in the oral cavity as periodontitis, gingivitis or lesions of the tooth hard tissues [4,5]. Understanding the mechanisms of bone metabolism under the action of thyroid hormones is an important aspect of treatment and diagnostic, as local treatment of dental pathology without reducing the impact on systemic factors does not have any positive result [6,7]. It is established that bone tissue is a constantly renewing tissue where remodeling processes take, place i.e. the processes of formation and destruction of osteotissue, pro- vided by osteoblasts, osteoclasts and osteocytes, which functional activity depends on exogenous and endogenous factors, some of which are О.V. Skochylo et al. ISSN 2413-6077. IJMMR 2021 Vol. 7 Issue 2 67 D e n t is t r y О.V. Skochylo et al. thyroid hormones. Although, according to Allen M.R. et al. [8] there are 2 types of remodeling. The first type – targeted remodeling, in which a specific local signal directs the osteoclast to a specific location to begin remodeling (e.g., in the areas of microdamage); the second – chaotic remodeling, a random process in which osteoclasts begin remodeling without any signaling. This type of recovery is significant in calcium homeostasis. At the cellular level, both types of remodeling are equal [8]. According to present scientists, the remodeling cycle has 5 stages (Fig. 1) [9]. In the first stage, the stage of activation, the stimulating signals by osteocytes and their transmission to cells of osteoclastic diferon are recognized. In response to this process, mo- nocytic-macrophage cells are attracted to the bone surface, stimulated, proliferated and differentiated into osteoclasts. At the heart of the molecular understanding of regulation, RANKL (receptor activator of nuclear factor kappa B ligand) is a transmembrane ligand of the nuclear factor activator receptor produced by osteoblasts that activates lymphocytes and macrophages. RANKL molecules may remain attached to the surface of osteoblasts or stro- mal cells for some time. RANK is a trans- membrane receptor of nuclear factor activator. RANKL interacts with RANK, which is accom- panied by the fusion of several osteoclast progenitor cells into one large structure and mature multinucleated osteoclasts are formed. Thus, osteoblasts regulate formation of osteo- clasts [11]. OPG-osteoprotegerin is a protein synthesized by osteoblasts and bone marrow stromal cells. It is proved that at the stage of osteoclast formation, the process can be blocked by the protein OPG-osteoprotegerin, which can bind to RANKL, that prevents for- mation of the RANKL/RANK complex and thus stops resorption processes [12]. According to recent studies [13], not only in osteoblasts but also in osteocytes, most of the recently synthesized RANKL form a protein complex with OPG and is selectively directed to lysosomes. Only a small fraction of newly synthesized RANKL, which does not form a complex with OPG, is transported to the cell surface. Subsequently, transmembrane RANKL is delivered to the surface of osteoclast pre- cursors to stimulate RANK, and induce activation of the subsequent signaling pathway. According to the authors, the ability of osteocytes to sup- port formation of mature osteoclasts probably depends on the number of RANKL molecules present on their cell surfaces. However, the way in which osteocytes embedded in the bone matrix deliver transmembrane RANKL to the cell surfaces of osteoclast precursors that are localized in the bone marrow cavity should be elucidated. The second stage is the stage of resorption ‒ due to production of enzymes osteoclasts destroy the bone matrix. According to some scientists, at this stage, activated osteoclasts are phagocytes for bone. Lysosomal collagenase is synthesized in large quantities that leads to disruption of the order in the structure of collagen. The products of hydrolysis enter the Fig. 1. Physiological bone remodeling, J.A. Siddiqui and N.C. Partridge [10]. ISSN 2413-6077. IJMMR 2021 Vol. 7 Issue 268 D e n t is t r y osteoblast from the “corrugated bristles” by endocytosis, and are released from the base- ment membrane, which is in contact with the blood vessel. The acidic environment in the area of resorption promotes leaching of calcium from apatites; the so-called “resorptive bone gaps” are formed; as a result, calcium and phosphates get into the blood. The third stage, the stage of reversion, osteoclasts undergo apoptosis, they are re- placed by mesenchymal cells, which differentiate into osteoblasts [15]. Active osteoclasts syn- thesize and secrete acid phosphatase, which dephosphorylates osteopontin, a sialoprotein that attaches to cells in the resorption zone. The connection with the bone surface becomes weak, so the resorption gradually decreases. A cementing line (a layer of secretory glyco- proteins) is formed on the resorbed surface, which is able to hold colonies of osteoblasts, an additional prerequisite for this is the availability of local osteoprogenitors [16]. The fourth stage, the stage of bone for ma- tion, osteoblasts synthesize the main organic substance of the bone matrix – collagen and substances that regulate mineralization (oste- calcin, osteonectin, etc.) [17]. The “matrix bubbles” of osteoblasts are significant in the process of mineralization. Amorphous Са3(РО4)2 is formed first in them, and later ‒ hydroxyapatite: “matrix bubbles”, which enter the extracellular space, contain high concentrations of calcium ions, according to Vavilova T.P., in 25-50 times more, than in osteoblasts, as well as enzymes: alkaline phosphatase, pyrophosphatase. In the intercellular matrix, membrane vesicles are destroyed with the release of calcium ions. Due to the influence of alkaline phosphatase, Са2+ ions combine with РО43-, resulting in the for- mation of amorphous calcium phosphate. At the same time, Са2+ and РО43- ions bind to colla- gen and non-collagen proteins and matrix is formed, which is accompanied by the formation of nuclei. On the formed nucleus there are spiral structures, the growth of which takes place on the principle of adding new ions. The step of such a spiral is equal to the height of one structural unit of the crystal. Crystal forma- tion leads to the appearance of other crystals, this process is called epitaxis or epitaxic enucleation [18]. Thus, mineralization occurs through the formation of calcium phosphate compounds that enter the bloodstream and their subsequent crystallization into hydroxyapatite followed by deposition of calcium hydroxyapatite along the collagen fibers [18]; osteoblasts play the main role in collagen synthesis [10]. The fifth stage, the final stage, is charac­ terized by differentiation of osteoblasts into osteocytes. After the bone formation stage is finished, the resting stage takes place, the osteoblasts are walled up in the matrix created in them, they lose activity and transform into osteocytes [19], which even recently were considered low metabolically active cells. But, as has been discovered, due to the mecha no- sensory properties that occur through the indu ced flow of fluid through the lacuno­tu bu­ lar system, they regulate remodeling processes [20] and, as studied by Cappuli [21], regulation is carried out by sclerostin protein (SOST), which inhibits osteoblast differentiation. The process of remodeling is regulated by numerous hormonal and local factors, neuro- endocrine and metabolic (Fig. 2) [10]: gluco­ corticoids reduce synthesis of osteoblasts, which slows down formation of bone tissue; the influence of thyroid hormones (thyroxine and triiodothyronine) increases activity of osteo- clasts, which contribute to catabolism of bone tissue. At the same time, sex hormones, espe- cially estrogens, have antiresorptive properties. Somatotropic hormone stimulates proliferation of osteoblasts and growth factors. It is estab- lished that with a decrease of the concentration of Са2+ ions in the blood the secretion of pa- rathyroid hormone (PTH) increases, which is produced by cells of the parathyroid glands, and under its influence activates osteoclasts in bone tissue that increases bone resorption. As Са2+ ions increase, the hormone calcitonin is secreted in the blood, which is produced by parafollicular thyroid cells and which bone mineralization increases and the number of osteoclasts reduces, i.e. resorption processes inhibits and, consequently, bone formation accelerates. Vitamin D is important in regulation of concentration of Са2+ ions in the blood, which are involved in the biosynthesis of Са2+-binding proteins required for intestinal calcium ab- sorption, renal reabsorption and mobilization of calcium from bones. Recently, evidence has emerged that vitamin D is involved in deve lop- ment of many autoimmune diseases, including patients with autoimmune thyroid disease (AITD) [22]. It is established that thyroid hormones directly affect both remodeling processes, as they activate both osteoblasts and osteoclasts, and the process of calcium-phosphorus me- О.V. Skochylo et al. ISSN 2413-6077. IJMMR 2021 Vol. 7 Issue 2 69 D e n t is t r y О.V. Skochylo et al. tabolism [24]. The thyroid gland secretes thyroxine (Т4), triiodothyronine (Т3) and cal- citonin. The functional activity of the gland is regulated by thyroid-stimulating hormone (TSH), which is synthesized by the pituitary gland in res ponse to the secretion of thyroliberin (TRG) by the hypothalamus. With a decrease in the con centration of thyroid hormones the secretion of TSH increases resulting in an increase in their formation in the thyroid gland, and, vice versa, with an increased concentration of thyroid hormones the formation of TSH decreases [17, 24]. Thus, this cooperation of the main endocrine gland functions on the principle of “negative feedback” that ensures a constant level of hormones. Violation of the concentration of one of the elements of the chain leads to changes in others that ultimately leads to dysfunction of both the endocrine glands and other organs and systems that depend on them. In the context of bone tissue, according to Pankiv I.V. [4], and as seen at the scheme, thyroid hormones affect bone metabolism by increasing the activity of osteoclasts, which contribute to bone catabolism. There are studies [4, 25, 26], in which the authors indicate of osteoporosis of bone tissue with underlying hypothyroidism. According to [4], in persons with thyroid pathology, changes in bone mi- neral density were detected in 59 (39.9%) cases: osteopenia ‒ in 45 (30.4%) and osteoporosis ‒ in 14 (9.5%) cases. The incidence of osteopenia and osteoporosis was likely to increase in all groups of patients with thyroid functional disorders. The main factor that leads to de- crease in bone strength in patients with thyroid disease is excessive or insufficient production Fig. 2. Systemic regulation and growth factor of bone remodeling, J. Siddiqui, N. Partridge [10]. ISSN 2413-6077. IJMMR 2021 Vol. 7 Issue 270 D e n t is t r y of thyroid hormones, as well as treatment with suppressive doses of levothyroxine. It is proved that the effect of thyroid hormones on the body cells is caused by the presence of receptors (TR) on their surface (Fig. 3). It is established that there are several types of thyroid receptors: TRα1, TRα2, TRβ1, TRβ2 [10]. It was established that only TRα and TRβ receptors on the surface of osteoblasts and chondrocytes were detected in bone cells [28]. Accordingly, Т3 (triiodo- thyronine) induces osteogenesis by direct action on osteoblasts. However, recent studies [29] have proved that expression of thyroid receptor (TR) genes α1 and β1 is confirmed in osteoclasts, but it is still indefinite whether tri­ iodothyronine (Т3) stimulates osteoclast activity directly or whether these processes are the result of Т3 action in osteoblasts, osteocytes or other cells. As for the TRβ2 receptor, there is evidence that it is associated with the hypothalamus and pituitary gland, where it inhibits the secretion of TRG and TSH, so the hypothalamic-pituitary- thyroid relationship is important in regulation of bone metabolism. To date, there are still debates on the key role in the functioning of bone tissue:by TSH or thyroid hormones [29]. The recommendations of the American Thyroid Association [30] state that serum TSH levels are one of the most informative indicators of thyroid function, and the Association recommends that all patients have serum TSH levels determined from the age of 35 and monitored every 5 years, which is an important diagnostic aspect. However, confirmation is found in the lite­ rature: hypothyroidism causes general hypo­ metabolism [31], a decrease in osteoblast for- ma tion and resorption of osteoclasts, and leads to low bone metabolism or slowing down the remodeling process. According to the author, the processes of osteo formation are slowed down by 50%, the processes of resorption – by 40% [31]. Calciuria decreases, serum concent- rations of osteocalcin and alkaline phosphatase decrease, but the concentration of parathyroid hormone and vitamin D in the serum may increase [31]. Analysing this data and drawing parallels with clinical symptoms, scientists patho gene- tically distinguish the following types of hypo- thyroidism: 1. Primary hypothyroidism caused by pri- mary pathology of the thyroid gland, which is divided into hypothyroidism due to a decrease in the amount of functionally active tissue of the gland and impaired biosynthesis of thyroid hormones. 2. Secondary (pituitary) hypothyroidism caused by a decrease in TSH production. 3. Tertiary (hypothalamic) hypothyroidism due to a decrease or production of thyroliberin. 4. Peripheral (tissue) resistance to thyroid hormones [24]. Autoimmune thyroiditis (AIT) is the most common cause of primary hypothyroidism [32]. Taking into account the complex mechanism of metabolic thyroid hormones metabolism, the question is whether thyroid dysfunction affects the course of oral diseases, the development of which is accompanied by destructive pro- cesses in bone tissue. Fig. 3. The thyroid gland secretes the prohormone T4 and the active hormone T3, and circulating concentrations are regu- lated by the classical endocrine cycle of negative feedback, which maintains the physiological feedback between TSH and Т4 and Т3. PVN, paraventricular nucleus (Bassett J.H, Williams G.R.) [28] О.V. Skochylo et al. ISSN 2413-6077. IJMMR 2021 Vol. 7 Issue 2 71 D e n t is t r y О.V. Skochylo et al. Periodontal diseases are foremost in the structure of dental pathology due to the sig - nificant spread among the population of Ukraine [33]. This pathology is characterized by inflam matory-destructive changes of the periodon tium, progressive nature of their course and leads to early tooth loss [34]. According to recent literature, the causes for this are both local and systemic factors [35], and sometimes a combi nation of both. Local factors include microbial film, small orifice of the mouth, pathology of the bridles and the existing strands of the mucous membrane, crowding of the teeth, impaired occlusion. Regarding the systemic factors that contribute to development of periodontal diseases, chronic cardiovascular, digestive and endocrine diseases are important. Most scien tists today are inclined to the domi nant role of the in- fluence of microorganisms and tissue in flam­ matory response as a con se quence of their activities [36]. The most com mon micro orga- nisms of the dental micro bial film are gram­ negative anaerobic bacteria Porphy romonas gingivalis, Tannerella forsythia, Treponema denticola, Prevotellaintermedia [37, 44]. The mechanism of action of micro orga nisms is explained by their penetration through the connective tissue epithelium of the gingival sulcus that disrupts the integrity of the gingival junction and affects the pe riodontal tissues located deeper [37]. In cases of the inflammatory process in the periodontium microcirculation is violated that is accompanied by an increase in vascular permeability with insudation of blood plasma proteins into the walls of blood vessels and perivascular tissue. It has been proved that pathology in periodontal vessels is a trigger for progression of periodon titis [38]. In a com pa rative study of the micro circulation of healthy patients and in the exa mi nation of persons with periodontitis of va rying severity (1-3 degrees), (127 people), according to laser Doppler flow metry, it was found that in pe­ riodontitis 1st degree severity, in hemody namics is decreased, compare to the healthy group of people, con gestion in the micro circulatory tract is present with further deve lopment of rheolo- gical disor ders. In generalized periodontitis of the 2nd degree, the main indicators of tissue blood flow are reduced, compare to the pre­ vious group, and in pe riodontitis of the 3rd degree microcir culatory disorders worsen with the involvement of all parts of compensatory regulation [38]. Thus, violation of micro circu- lation in the presen ce of microbial mechanisms leads to slowing of blood flow, venous stasis, impaired vascular transport [40]. Due to the possible systemic effects of thyroid dysfunction, periodontal tissue micro- circulation in this aspect was studied by Scar- dina G.A., Messina P. (2008) [41], who assessed morphological microcirculation of interdental papillae in patients with Hashimoto’s thyroiditis and possible associated periodontal disease. It was emphasized that the group of healthy patients deliberately did not involve the persons with conditions that disrupt micro- circulation, such as diabetes or hypertension. All patients did not smoke. Microcirculation was assessed by capillaroscopy. For each patient, visibility, course, tortuosity, average capillary loop size and number of visible capillary loops per square millimeter were investigated. In patients with Hashimoto’s thyroiditis, a re- duced capillary caliber, as well as a greater number and tor tuosity of capillary loops were evidenced. This study showed that changes in the capillaries in patients with Hashimoto's thyroiditis occur red in cases of violation of gums microcirculation that is characteristic of periodontitis. The opinion that periodontitis is a multi- factorial disease with a microbial initiator, the manifestation and progression of which is predisposed by a wide range of factors, one of which is Hashimoto’s thyroiditis, is more and more popular [42, 43]. According to Molaris A. et al. [42], after analyzing the data of 30 articles on the relationship between periodontitis and Hashimoto’s thyroiditis regarding etiopatho- genetic mechanisms, have established that it occurs because some of these mechanisms are accompanied by vascular endothelial dys- function, microcirculation disorders, as well as due to the impact of hypothyroidism on alveolar protease metabolism, but a causal relationship between the two nosologies requires further research. According to Patil B., Patil S., Gururaj, T. (2011) [7], their study was initiated due to the lack of effective local therapy of periodontitis in thyropatients. Kothiwale S. et al. [5] presented a very interesting study regarding the impact of thyroid hormone dysfunction on the prog- ression of periodontitis, systemic health of the patient, in which local treatment of periodontal tissues as a complex with endocrine com- pensation was proved. It was emphasized that the etiotropic phase of dental treatment lasted 8 weeks with the prescribed 150 mg of systemic thyroxine per day. During the dynamic ob- ISSN 2413-6077. IJMMR 2021 Vol. 7 Issue 272 D e n t is t r y servation, the hygienic index of the oral cavity improved, but the bleeding did not disappear. After 12 weeks of follow-up, after stabilization of thyroid hormones, a clear decrease in gin- gival bleeding was evidenced. The need for frequent professional evaluation, training of patients, motivating them to frequent syste- matic examinations was emphasized, as the treatment of such patients and achieving long- term remission would provide a positive result only in endocrinologist-dentist tandem. According to Brankhar R.R. et al. (2017) [43] the endocrine system works together with the immune system. Despite the fact that the bila- teral effects of systemic diseases on the perio- dontium are proved, there are a few studies on the effects of periodontal therapy on hormone levels. In the study, the effect of non-surgical periodontal therapy (NSPT) on serum stimu- lating hormone (TSH) levels in patients with hypothyroidism and periodontitis was assessed. Clinical parameters and serum TSH levels were recorded at baseline in the experimental and control groups and compared with TSH data in 3 months after NSPT in the patients with hypo- thyroidism. The results of the study showed that NSPT was significant in improving the condition of the periodontium by reducing inflammatory markers and thus affecting thyroid hormone, a significant decrease in TSH in patients with hypothyroidism in 3 months after NSPT. Chingiz Ragim Ogly Rakhimov, (2020) [44] presented data on the clinical efficacy of hyaluronic acid in the treatment of periodontal disease in patients with hypothyroidism. Accor- ding to the evaluation of the main hygienic and periodontal indices, it was found that a decrease in the content of thyrohormones led to an increase in the frequency and inflam ma­ tory-destructive forms of periodontal disease. In such patients, high-frequency of Porphyro- monasgingivalis (25% and 15% in somatically healthy patients) and increased colonization of yeast-like fungi of the genus Candida albicans were evidenced in the oral cavity. After the treatment, there was a positive clinical dynamic, but in patients with impaired gland function had worsening of the oral cavity in a month that confirmed the idea of ineffectiveness of only local dental treatment and the need for dyna- mic monitoring of hormonal status. There are studies on effectiveness of intra- ligamentous administration of vitamin D and calcium in the treatment of chronic periodontitis associated with hypothyroidism. In 3 months, there was a significant decrease in mobility, pocket depth and bleeding in the treatment of chronic periodontitis associated with hypo- thyroidism. The need for clinical trials with a large sample size and long-term observations was emphasized [45]. The significance of vita­ min D in the development of autoimmune thyroiditis was covered by Bizzaro G. et al. [46, 47]. There is no doubt that patients with estab- lished hypothyroidism need a replacement therapy, and the study of periodontal status when taking thyroxine is the basis of further research [48]. After analyzing the plaque index, bleeding index, pocket probing depth [PPD], level of clinical attachment [CAL] and radiological parameters, in the study group (52 patients) statistically significantly higher PPD and loss of clinical attachment compare to the control group was established. With the beginning of treatment of periodontitis and hypothyroidism improvement in oral hygiene and a decrease in bleeding gums was evidenced. Regression analysis showed that hypothyroidism and thyroxine replacement therapy were important predictors of PPD and CAL, but it still requires further study. The same opinion is traced in the study by Hajer A. Aldulaijan et al. (2020), who analyzed 847 publications and applied their inclusion and exclusion criteria; thus only 29 publications were selected, which were more critically analyzed. As a result, only four pub- lications were used to further assess the hypo- thyroidism-periodontitis relationship, including one research note on association between hypothyroidism and periodontitis. Hence, further well-controlled, clinical and immu no- logical studies are needed to confirm this relationship [6]. Conclusions The results of the studies prove that there is a significant effect of the thyroid gland on the state of the oral cavity that can be manifested by periodontitis, which is accompanied by bone destruction and inflammatory processes in the gum tissue. Local treatment of dental pathology without correction of thyrohormonal status does not provide effective treatment, so the correct diagnosis, selection of treatment and medical cooperation of a dentist and endo- crinologist is necessary. Such disorders are common, but there is still a lack of accurate and improved examinations of this problem, which will be the goal of our further research in the future. О.V. Skochylo et al. ISSN 2413-6077. IJMMR 2021 Vol. 7 Issue 2 73 D e n t is t r y О.V. Skochylo et al. Conflict of Interests Authors declare no conflict of interest. Authors’ Contributions Olha Skochylo – investigation, formal ana- lysis, writing – original draft. Svitlana Boitsanyuk – formal analysis, writing – reviewing and editing, data curation. Nataliya Tverdokhlib – conceptua- lization, methodology, writing – reviewing and editing. ОСОБЛИВОСТІ МЕТАБОЛІЧНОГО ОБМІНУ У КІСТКОВІЙ ТКАНИНІ ТА ЗМІНИ ЗІ СТОРОНИ РОТОВОЇ ПОРОЖНИНИ НА ГРУНТІ ЗНИЖЕННЯ ФУНКЦІОНАЛЬНОЇ АКТИВНОСТІ ЩИТОПОДІБНОЇ ЗАЛОЗИ (огляд літератури) *О.В. Скочило, С.І. Бойцанюк, Н.О. Твердохліб ТЕРНОПІЛЬСЬКИЙ НАЦІОНАЛЬНИЙ МЕДИЧНИЙ УНІВЕРСИТЕТ ІМЕНІ І.Я. ГОРБАЧЕВСЬКОГО МОЗ УКРАЇНИ, ТЕРНОПІЛЬ, УКРАЇНА Вступ. Зниження функціональної активності щитоподібної залози залишає свій слід на багатьох органах та системах. Не виключенням є і кісткова тканина, патологічні зміни якої в ротовій порожнині найчастіше спостерігаємо при пародонтитах. Проте, все ще залишається не підтвердженим взаємозв'язок між гіпофункцією тиреоїдної залози та пародонтитом чи іншими запальними захворюваннями ротової порожнини. Метою нашого огляду власне, і було дослідження опублікованої інформації та її аналіз щодо метаболізму кісткової тканини та її взаємозв'язоку між автоімунним тиреоїдитом та захворюваннями ротової порожнини. Методи. Науковими джерелами були статті у зарубіжних періодичних виданнях з ендокринології, патофізіології, хірургічної, терапевтичної стоматологій. Результати. Розуміння механізмів кісткового метаболізму під дією гормонів щитовидної залози є важливим аспектом лікувально-діагностичного процесу, оскільки місцеве лікування стоматологічної патології без виключення впливу на системні чинники у підсумку не дає позитивного результату. Зниження функціональної активності щитоподібної залози призводить до дисбалансу в гомеостазі організму. Оскільки гормони щитоподібної залози відіграють важливу роль у обміні кісткової тканини, то найчастіше зустрічаються публікації стосовно виникнення пародонтиту на фоні автоімунної патології щитоподібної залози. Проте, незважаючи на існуючі дослідження та зафіксовані зміни, більшість авторів згідні з думкою, що таких досліджень на даний час є недостатньо, щоб чітко встановити причинно-наслідковий взаємозв’язок між автоімунним процесом щитоподібної залози та патологією щелепно-лицевої ділянки. Висновки. Представлені дані розширюють існуючі знання, проте все ще існує потреба в подальших сучасних детальних дослідженнях, які б чітко дали відповідь на механізми виникнення та розвитку взаємозв'язку між автоімунною патологією щитоподібної залози та станом кісткової тканини ротової порожнини. КЛЮЧОВІ СЛОВА: пародонтит; щитоподібна залоза. Information about the authors Olha V. Skochylo – PhD, MD, Associate Professor of the Department of Dental Surgery, I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine. ORCID 0000­0002­8621­8275, e­mail: skochyloov@tdmu.edu.ua Svitlana I. Boitsanyuk – PhD, MD, Associate Professor of the Department of Dental Therapy, I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine. ORCID 0000­0001­7742­1346, e­mail: boucanuk@tdmu.edu.ua Nataliya O. Tverdokhlib – PhD, MD, Associate Professor of the Department of Dental Surgery, I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine. ORCID 0000­0002­1247­2430, e­mail: tverdohlibno@tdmu.edu.ua ISSN 2413-6077. IJMMR 2021 Vol. 7 Issue 274 D e n t is t r y References 1. Kravchenko VI. Iodine deficiency as a cause of high prevalence of thyroid pathology in the popu- lation of regions affected by the chernobyl accident. Zhurnal NAMN Ukrainy. 2016;22(2):222­9 [in Ukrainian]. 2. Chukur OO. Dynamics of morbidity and pre- valence of thyroid pathology among the adult population of Ukraine. Bulletin of social hygiene and health care organization of Ukraine. 2018;4(78):19­25 [in Ukrainian]. 3. Vladymyrova IM, Heorhiiants VA. Farmako- terapevtychni napriamky zastosuvannia yodo- vmisnykh likarskykh roslyn pry riznykh hrupakh zakhvoriuvan shchytopodibnoi zalozy [Pharma- cotherapeutic directions of application of iodine- containing medicinal plants in different groups of diseases of the thyroid gland]. Scientific Journal “ScienceRise”. 2015;11/4 (16):46­54 [in Ukrainian]. 4. Pankiv IV. Influence of the functional state of the thyroid gland on bone mineral density. Trauma. 2015;6(16):33­41 [in Ukrainian]. 5. Kothiwale S, Panjwani V. Impact of thyroid hormone dysfunction on periodontal disease. J Sci Soc. 2016;43:34­47. 6. Aldulaijan HA, Cohen RE, Stellrecht E, Levine MJ. Relationship between hypothyroidism and perio- donti tis: A scoping review. Clin Exp Dent Res. 2020;6:147­57. https://doi.org/10.1002/cre2.247 7. Patil B, Patil S, Gururaj T. Probable autoimmune causal relationship between periodontitis and Hashimotos thyroidits: A systemic review. Nigerian journal of clinical practice. 2011;14:253­61. https://doi.org/10.4103/1119­3077.86763. 8. Allen MR, Burr DB. Bone Modeling and Remo- de ling. Basic and Applied Bone Biology 2014;Chap- ter 4:75­90. 9. Kenkre JS., Bassett J. The bone remodelling cycle. Ann Clin Biochem. 2014;55(3):308­27. https://doi.org/10.1177/0004563218759371. 10. Siddiqui JA, Partridge NC. Physiological Bone Remodeling: Systemic Regulation and Growth Factor Involvement. Physiology (Bethesda), May, 31 (3). 2016;233-45. DOI:10.1152/physiol.00061.2014. 11. Martin TJ, Sims NA. RANKL/OPG; Critical role in bone physiology. Rev Endocr Metab Disord, Jun. 2015;16(2):131­9. https://doi.org/10.1007/s11154­014­9308­6. 12. Walsh MC, Choi Y. Biology of the RANKL- RANK-OPG System in Immunity, Bone, and Beyond. Front Immunol. Oct 20; 5, 511. 2014. https://doi.org/10.3389/fimmu.2014.00511. 13. Honma M, Ikebuchi Y, Suzuki H. Mechanisms of RANKL delivery to the osteoclast precursor cell surface. J Bone Miner Metab. 2021;Jan 39(1):27­33. https://doi.org/10.1007/s00774­020­01157­3. 14. Kiyoi T. Bone Resorption Activity in Mature Osteoclasts. Methods Mol Biol. 2018;1868:215­22. https://doi.org/10.1007/978­1­4939­8802­0_22. 15. Horwood NJ. Macrophage Polarization and Bone Formation: A review. Clin Rev Allergy Immunol. 2016;Aug;51(1):79­86. https://doi.org/10.1007/s12016­015­8519­2. 16. Delaisse JM. The reversal phase of the bone- remodeling cycle: cellular prerequisites for coupling resorption and formation. Bonekey Rep. 2016;5:856. https://doi.org/10.1038/bonekey.2016.88. 17. Kini U, Nandeesh BN. Physiology of Bone Formation, Remodelling, and Metabolism. In: Fogelman, I., Gnanasegaran, G. and Wall, H., Eds., Radionuclide and Hybrid Bone Imaging, Springer, Berlin, Heidelberg. 2012;29-57. 18. Nudelman F, Pieterse K, George A, Bomans PH, Friedrich H, Brylka LJ, Hilbers PA, de With G, Som- mer dijk NA. The role of collagen in bone apatite formation in the presence of hydroxyapatite nuclea- tion inhibitors. Nat Mater, 2010;Dec;9(12):1004­9. https://doi.org/10.1038/nmat2875. 19. Wu V, van Oers RFM, Schulten EA JM, Helder MN, Bacabac RG, Klein-Nulend, J. Osteocyte morphology and orientation in relation to strain in the jaw bone. Int J Oral Sci. 2018;Feb 26, 10(1):2. https://doi.org/10.1038/s41368­017­0007­5. 20. Klein-Nulend J, Bakker AD, Bacabac RG, Vatsa A, Weinbaum S. Mechanosensation and transduction in osteocytes. Bone. 2013;54:182­190. https://doi.org/10.1016/j.bone.2012.10.013. 21. Capulli N, Paone R, Rucci N. Osteoblast and osteocyte: Games ithout frontiers. Arch Biochem Biophys. 2014;Nov 1,561:3­12. https://doi.org/10.1016/j.abb.2014.05.003. 22. Bizzaro G., Shoenfeld Y.Vitamin D and auto- immune thyroid diseases: facts and unresolved questions. Immunol Res. 2015;61(1­2):46­52. https://doi.org/10.1007/s12026­014­8579­z. 23. Gromova OA, Torshin IYU, Limanova OA. Mnogogrannaya rol’ makro- i mikroyelementov v postroyenii kostnoy tkani. Ginekologiya. 2014;2:50­6. https://doi.org/10.26442/2079­5831_16.2.50­56. 24. Panʹkiv VI. Syndrom hipotyreozu. Mezhdu­ narodnyy éndokrynolohycheskyy zhurnal, 2012; 5(45):136­48. 25. Polovina SP, Miljic D, Zivojinovic S, Milic N, Micic D, Brkic VP. The impact of thyroid autoimmunity (TPOAb) on bone density and fracture risk in post- menopausal women. Hormones (Athens, Greece), 2017;16(1):54­61. https://doi.org/10.14310/horm.2002.1719. 26. Lee K, Lim S, Park H, Woo HY, Chang Y, Sung E, Jung HS, Yun KE, Kim CW, Ryu S, Kwon MJ. Subclinical thyroid dysfunction, bone mineral density, and osteoporosis in a middle-aged Korean population. Osteoporosis international: a journal established as result of cooperation between the European Foun- dation for Osteoporosis and the National Osteopo- rosis Foundation of the USA. 2020;31(3):547­55. https://doi.org/10.1007/s00198­019­05205­1. 27. Baliram R, Latif R, Zaidi M, Davies TF. Expanding the Role of Thyroid-Stimulating Hormone in Skeletal Physiology. Front. Endocrinol. 2017;8:252. https://doi.org/10.3389/fendo.2017.00252. О.V. Skochylo et al. ISSN 2413-6077. IJMMR 2021 Vol. 7 Issue 2 75 D e n t is t r y О.V. Skochylo et al. 28. Bassett JH, Williams GR. Role of Thyroid Hormones in Skeletal Development and Bone Maintenance. Endocr Rev. 2016;37(2):135­87. https://doi.org/10.1210/er.2015­1106. 29. Duncan Bassett JH, Williams GR. Analysis of Physiological Responses to Thyroid Hormones and Their Receptors in Bone. Methods in molecular biology (Clifton, N.J.). 2018;1801:123­54. https://doi.org/10.1007/978­1­4939­7902­8_12. 30. Ladenson PW, Singer PA, Ain KB, Bagchi N, Bigos ST, Levy EG, Smith SA, Daniels GH, Cohen HD. American Thyroid Association guidelines for detec- tion of thyroid dysfunction. Archives of internal medicine. 2020;160(11):1573­5. https://doi.org/10.1001/archinte.160.11.1573. 31. Kosińska A, Syrenicz A, Kosiński B, Garanty­ Bogacka B, Syrenicz M, Gromiak E. Osteoporoza w chorobach tarczycy. Endokrynol Pol. 2005;2:185­93. 32. Sheremet MI, Shidlovskiy VА, Sydorchuk LP. Autoimmune thyroiditis. Modern views on the patho- genesis and treatment (literature review). Endocry- nologia. 2014;19(3):227­35. [in Ukrainian]. 33. Mazur IP, Pavlenko OV. The current state of dental care in Ukraine Health of Ukraine. 2017;18 (415):74­5. [in Ukrainian]. 34. Nazir MA. Prevalence of periodontal disease, its association with systemic diseases and prevention. International journal of health sciences. 2017;11(2): 72-80. 35. Borgnakke WS. Does Treatment of Periodontal Disease Influence Systemic Disease? Dental clinics of North America. 2015;59(4):885­917. https://doi.org/10.1016/j.cden.2015.06.007. 36. Kowalski J, Górska R. Clinical and micro- biological evaluation of biofilm­gingival interface classification in patients with generalized forms of periodontitis. Polish Journal of Microbiology. 2014; 63(2):175­181. 37. Kang W, Hu Z, Ge S. Healthy and Inflamed Gingival Fibroblasts Differ in Their Inflammatory Response to Porphyromonas gingivalis Lipopoly- saccharide. Inflammation. 2016;39(5):1842­52. https://doi.org/10.1007/s10753­016­0421­4. 38. Onyshchenko VS, Ovcharenko OM, Trofy- menko OA. Lazerna dopplerivsʹka floumetriya v otsintsi pokaznykiv mikrotsyrkulyatsiyi pry zakhvo- ryuvannyakh tkanyn parodontu na riznykh etapakh ortopedychnoho likuvannya // Materialy nauk.-prakt. konf. z mizhnar. uchastyu, XII zasidannya Ukrayinsʹko­ ho Dopplerivsʹkoho Klubu “Ulʹtrazvukova ta funk­ tsionalʹna diahnostyka v anhiolohiyi”. 2006;46­8. 39. Lira-Junior R, Figueredo CM, Bouskela E, Fischer RG. Severe chronic periodontitis is associated with endothelial and microvascular dysfunctions: a pilot study. Journal of periodontology. 2014; 85(12):1648­57. https://doi.org/10.1902/jop.2014.140189. 40. Zyul’kina LA, Sabayeva MN, Ivanov PV, Shastin YeN. Mikrotsirkulyatsiya tkaney parodonta: prichiny narusheniy i mekhanizmy korrektsii. Sovre- mennyye problemy nauki i obrazovaniya. 2017;2. 41. Scardina GA, Messina P. Modifications of interdental papilla microcirculation: a possible cause of periodontal disease in Hashimoto’s thyroiditis? Ann Anat. 2008;190(3):258­63. https://doi.org/10.1016/j.aanat.2007.12.004. 42. Morais AМ, Pereira J. Hashimoto Thyroiditis and Periodontal Disease: A Narrative Review. Acta Médica Portuguesa. 2016;29(10):651­7. https://doi.org/10.20344/amp.6704. 43. Bhankhar RR, Hungund S, Kambalyal P, Singh V, Jain K. Effect of nonsurgical periodontal therapy on thyroid stimulating hormone in hypo- thyroid patient with periodontal diseases. Indian J Dent Res. 2017;2:16­21. https://doi.org/10.4103/ijdr.IJDR_174_16. 44. Rakhymov CHR. Likuvalʹno­profilaktychni osoblyvosti zakhvoryuvanʹ parodonta u khvorykh na hipotyreoz. Suchasna stomatolohiya. 2020;1:34­8. https://doi.org/10.33295/1992­576X­2020­1­34. 45. Yussif NM, El-Mahdi FM, Wagih R. Hypo- thyrodism as a risk factor of periodontitis and its relation with vitamin D deficiency: mini­review of literature and a case report. Clin Cases Miner Bone Metab. 2017;14(3):312­6. https://doi.org/10.11138/ccmbm/2017.14.3.312. 46. Bizzaro G, Shoenfeld Y. Vitamin D and autoimmune thyroid diseases: facts and unresolved questions. Immunol Res. 2015;Feb;61(1­2):46­52. https://doi.org/10.1007/s12026­014­8579­z. 47. Tuchendler D, Bolanowski M. The influence of thyroid dysfunction on bone. Thyroid Research. 2014;7:12. https://doi.org/10.1186/s13044­014­0012­0. 48. Rahangdale SI, Galgali SR. Periodontal status of hypothyroid patients on thyroxine replacement therapy: A comparative cross­sectional study. J Indian Soc Periodontol. 2018;22(6):535­40. https://doi.org/10.4103/jisp.jisp_316_18. Received 19 November 2021; revised 26 November 2021; accepted 7 December 2021. This is open access article distributed under the Creative Com- mons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.