During orthodontics treatment often drugs are prescribed to mange pain from force application to biological tissues, manage TMJ problems and tackle some infection throughout course of treatment. Apart from theses drugs, patients who consume vitamins, minerals, hormonal supplements and other compounds for the prevention or treatment of various diseases can also found in every orthodontic practice. Some of these drugs may have profound effects on the short and long term outcomes of orthodontic practice. Hence it is necessary to review the mechanism of action and effects of commonly used drugs on tissue remodeling and orthodontic tooth movement. According to WHO (1966), Drug is any substance or product that is used to modify or explore physiological systems or pathological states for the benefit of the recipient.
Analgesic is a drug that selectively relieves pain by acting on the CNS (Central Nervous System) or peripheral pain mechanisms, without significantly altering consciousness. NSAID’s do not affect the tenderness induced by direct application of PG ‘s, but block the pain sensitizing mechanism induced by bradykinins, TNF’s, IL’s etc. NSAID’s (Non Steroid Anti Inflammatory Drug) reduce body temperature in fever, but donot cause hypothermia in normothermic individuals. NSAID’s block the pyrogenic actions of ILs, TNF’s, IF’s which induce PG production in hypothalamus. The analgesic action is mainly due to obtunding of peripheral pain receptors and prevention of PG medicated sensitization of nerve endings. NSAID are a relatively weak inhibitor of PG Synthesis and anti – inflammatory action may be exerted by reduced generation of superoxide by neutrophils, and TNF release, free radicle scavanging, inhibition of metalloprotease activity in cartilage.
Effect of NSAID’S on tooth movement
Most commonly used medications used in orthodontics, for control of pain following mechanical force application to tooth. PG’s are a product of arachdonic acid metabolism, are local hormone like agents produced by mammal cells, osteoblasts after cell injury. These 20 carbon atom EFA molecules are important as mediator of inflammatory response, which facilities tooth movement. Inhibition of this inflammatory reaction slows the tooth movement. Recent research demonstrated the molecular mechanisms behind the inhibition of tooth movement by NSAID ‘s. The levels of Matrix Mettallo – proteinnases (MMPs) -9 and (MMPs) – 2 were found to be increased, along with elevated colagenase activity, followed by a reduction in procollagen synthesis which are essential for bone and periodontal remodeling.The whole process is controlled by inhibition of COX activity leading to altered vascular and extra vascular matrix remodeling, causing a reduction in the pace of the tooth movement. Acetylsalicylic acid and the related compounds, their action results from inhibition of cyclooxygenase activity, which converts unsaturated fatty acids in cell membrane to prostaglandins. Clinical experience shows that orthodontic tooth movement is very slow in patients undergoing longterm acetylsalicylic therapy. Salicylate therapy decrease bone resorption by inhibition of PG’s synthesis and may effect differentiation of osteoclasts from their precursors. Therefore, it is recommended that patients undergoing orthodontic treatment, should not be advised to take aspirin & related compounds for longer period during orthodontic treatment.
An interesting recent development seen in prescriptions of a specific COX – 2 inhibitor, a drug with no effect on PGE2 synthesis. These drugs selectively block the COX2 enzyme, and impede the production of PG’s that cause pain and swelling. Because they selectively block COX2 enzyme not COX1 enzyme, it was suggested that it can be safely employed during orthodontic mechanotherpy, without causing negative effects on tooth movement. This drug is no more prescribed due to risk of cardiovascular events. A recent study reported that nabumetone, a belonging to NSAID group, reduces the amount of root resoption along with control of pain from intrusive orthodontic forces, without affecting the pace of tooth movement.
A weak COX-1 and COX-2 inhibitor that also reduces urinary prostaglandin levels after systemic administration has shown no effect on orthodontic tooth movement in guinea pigs and rabbits. Comparative studies and clinical experience shown that acetaminophen is effective for controlling pain and discomfort associated with the Orthodontic treatment.
Vitamin – D
Vitamin D is collective name given to anti – rachitic substances synthesized in the body and found in dietary sources activated by UV radiation. Vitamin D and its active metabolite, which is 1,25 2(OH) D3, together with Parathyroid hormone and caclitonin, reegulates the amount of calcium and phosphorus levels.
Effects of vitamin- D on bone and tooth movement
Some authors consider vitamin D3 to be a bone resorption-promoting agent because of it’s stimulatory effects on osteoclasts. Vitamin D receptors have been demonstrated not only in osteoblasts but also in osteoclast precursors and in active osteoclasts. In 1988, Collins and Sinclair demonstrated that intraligamentary injections of vitamin – D metabolite, 1,25 – dihydroxy cholecalciferol caused increase in the number of osteoclasts and amount of tooth movement during canine retraction with light forces. In 2004 kale and colleagues observed that the local applications of vitamins enhanced the rate of tooth movement in rats due the well balanced bone turnover induced by vitamin – D.
Stimulatory action of vitamin-D on osteoblasts can help stabilize orthodontic tooth movement. In 1976 study by Bran and colleagues , treated rates with vitamin – D, showed increased bone formation on pressure side of the PDL after application of orthodontic forces. In 2004, Kaakaami observed an increase in the mineral appositional rate on alveolar bone after orthodontic force application, they suggested that local application of Vitamin – D could intensify the reestablishment of supporting alveolar bone, after orthodontic treatment .
Fluoride is a one the trace element that effect had tissue metabolism. Fluoride increase bone mass, mineral density and because of these skeletal actions it has been used in treatment of metabolic bone disease, osteoporosis. Even a very active caries treatment with sodium fluoride during orthodontic treatment may delay orthodontic tooth movement and increase the time of orthodontic treatment. Sodium fluoride has been shown to inhibit the osteoclastic activity and reduce number of active osteoclasts.
Bisphosphonates have strong chemical affinity to the solid–phase surface of calcium phosphate, this causes inhibition of hydroxyapatite aggregation, dissolution and crystal formation. Bisphosphonates causes raise in intra–cellular calcium levels in osteoclastic like cell line. Reduction of osteoclastic activity, prevention of osteoclastic development from hematopoietic precursors and production of an osteoclast inhibitory factor.
Studies have shown that BPN’s can inhibit orthodontic tooth movement and delay the orthodontic treatment. Topical application of BPN’s could be helpful anchoring and retaining teeth under orthodontic treatment. A significant potential side effect of BPN’s is the development of osteo–necrosis in the mandible or maxilla particularly related to i.v. theraphy or high dose, long term, oral usage. This adverse effect is due to death of osteoclasts along with bone related capillary inhibition, decreasing microcirculation to the maxilla or mandible.
These are the biologically active derivative of 20 carbon atom PUFA’s that are released from cell membrane phospholipids. There are 2 major lipid derived Autocoids.
Most of the tissues are capable of synthesizing PG’s from the dietary essential fatty acids. PG’s released due to mechanical, chemical, thermal & bacterial insults. Both PGE 2 and PGI 2 are the potent vasodilators & hyperalgesic agents. PGE2 is also potent pyrogenic substance. PG’s play important role in inflammatory response.
Effect of PG’s on bone & tooth movement
Experiments have shown that PG’s may be mediators of mechanical stress during orthodontic tooth movement. They stimulate bone resorption, root resorption, decreased collagen synthesis and increase cyclic AMP. They stimulate bone resorption by increasing the number of osteoclasts and activating already existing osteoclasts. A lower concentration of PGE 2 (0.1 – microgram) appears to be effective in enhancing tooth movement. Higher concentration leads to root resorption. Systemic administration is reported to have better effect than local administration.
Leukotrienes are the metabolites of Arachidonic acid, they are produced when arachidonic acid is metabolized by the enzyme lipo-oxygenase. It is produced by limited number of tissues, mainly by LTB4 neutrophils (LTC4 <D4 – cysteiny1) LT s by macrophages. It sensitizes afferent carrying pain impulses, causes pain and tenderness at the site of inflammation. It constricts smooth muscle, important mediator in allergic asthma .
Effects on bone and tooth movement.
LTs important mediators of orthodontic tooth movement. It stimulates bone resorption. This role is clearly demonstrated when inhibitors of LTs synthesis are used in experiment model.
Echistatin and RGD Peptides
Another approach made recently is local injection of integrin inhibitors like Echistatin and RGD (Arginine – glycine – aspartic acid) peptides on rats to prevent tooth movement, thereby enhancing anchorage. Recent research has demonstrated decrease in root resorption following orthodontic force application after administration of Echistatin.
Estrogens are considered to be most important hormone to effect bone metabolism in women. It controls bone remodeling during reproductive life, and maintenance of maximum bone mass after menarche. Estrogen results in decreasing the rate of bone resorption. Estrogen inhibit the production of various cytokines, mainly interleukin – (IL-1), (TNF-a) tumor necrosis factor – alpha, and interleukin – 6(IL-6),which are involved in bone resorption by stimulating osteoclast formation and osteoclast bone resorption. According to population based study, deficiency in estrogen seems to be responsible for the secondary hyperparathyroidism found in postmenopausal women, as they also inhibit osteoblasts responsiveness to parathyroid hormone. Estrogens do not have any anabolic effects on bone tissue,; they directly stimulate the bone forming activity of osteoblasts.
Effects of estrogens on tooth movement
Studies have shown that, estrogens decrease the velocity of tooth movement. Oral contraceptive, taken for long periods of time, can influence the rate of tooth movement. Androgens also inhibit bone resorption and modulate the growth of the muscular system, may affect the length and results of the Orthodontic treatment .
Thyroid hormones are recommended for the treatment Hypothyroidism and used after thyroidectomy in substitutive theraphy. Thyroxin administration lead to increased bone remodeling, increased bone resorptive activity and reduced bone density. Effects on bone tissue may related to the augmentation of interleukin-1 (IL – 1B), production that thyroid hormones induce at low concentrations, cytokine stimulate osteoclast formation and osteoclastic bone resorption.
The skeletal actions of thyroid hormones increases the speed of orthodontic tooth movement in patients undergoing such medication. Low – dosage and shorterm thyroxin administration are reported to lower the frequency of ‘’ force induced ‘’ root resorption. Decrease in resorption may be correlated to a change in bone remodeling process and a reinforcement of the protection of the cementum and dentin to "force induced" osteoclastic resorption.
Relaxin has been known as a pregnancy hormone. It is released just before child birth to loosen the public sympysis, so that the relaxed suture will allow widening of the birth canal for parturition. Other actions, include the regulation of vasotonus, plasma osmolarity, angiogenesis, collagen turnover, and renal function. Relaxin influence on soft tissue remodeling and several mediators that stimulate osteoclasts formation. In 2005, Liu and colleagues showed that the administration of Relaxin might accelerate the early stages of orthodontic tooth movements in rats.
Effects of Relaxin on bone and tooth movement
Stewart and colleagues used gingival injections of Relaxin to relieve rotational memory in the connective tissues of maxillary lateral incisors that had been orthodontically rotated. In 2000, Nicozis and colleagues suggested that Relaxin might be used as an adjutant to orthodontic therapy, during or after tooth movement, for promotion of stability, for rapid remodeling of gingival tissue during extraction space closure, for orthopedic expansion in non – growing patients, by reducing the tension of the stretched soft tissue envelope, particularly the expanded palatal mucosa, after orthognathic surgery.
Calcitonin is a peptide hormone secreted by thyroid in response to hypocalcaemia. It is produced by parafollicular ‘C’cells of thyroid. Synthesis and secretion of Calcitonin is regulated by plasma calcium concentration. Rise in plasma calcium increases, while fall in plasma calcium decreases Calcitonin release. Calcitonin inhibits proximal tubular calcium and phosphate reabsorption by direct action on kidney. Calcitonin is used in the treatment of hypercalcemia, osteoporosis and pager’s disease of bone.
The effects of Calcitonin on bone and tooth movement.
Calcitonin inhibits bone resorption by direct action on osteoclasts decreasing their ruffled surface which forms contact with resorptive pit. It also stimulates the activity of osteoblasts. Because of its physiological role, it is considered to inhibit the tooth movement, consequently delay in orthodontic treatment can be expected.
Parathyroid Hormone (PTH)
Parathyroid hormone is produced by parathyroid glands to regulate serum calcium concentration. In kidneys, PTH increase renal calcium resorption and stimulates the excretion of urinary phosphate. In bone, PTH can induce a rapid release of calcium, but also mediates longer term changes by acting directly on osteoblasts & indirectly on osteoclasts. PTH affects osteoblasts cellular metabolic activity, gene transcriptional activity, and multiple protease secretion. Its effects on osteoclasts occur through the production of RANK – L, a protein play a crucial role in osteoclasts formation and activity.
Effect of PTH on tooth movement
In 1970s, animal studies demonstrated that PTH could induce an increase in bone turnover that would accelerate orthodontic tooth movement. More recently, observed an increased rate of tooth movements in rats treated with PTH, whether administered systemically or locally. These results indicate that orthodontists should take note of patients being treated with PTH – for example, in cases of severe osteoporosis.
The adrenal cortex secretes steroid hormones which have glucocorticoids, mineralocorticoid and weakly androgenic activities. The corticoids are 21carbon compounds having cyclopentanoperhydro – phenantherene (steroid) nucleus, they are synthesized in adrenal cortical cells from cholesterol. Adrenal- steroidogenesis takes place under the influence of ACTH which makes more cholesterol available for conversion to pregenenolone and induces steroidogenic enzymes.
Effects of corticosteroids on bone and tooth movement
Evidence indicates that the main effect of corticosteroid on bone tissue is direct inhibition of osteoblastic function and thus the decrease of total bone formation. Decrease in bone formation is due to elevated parathyroid hormone levels caused by inhibition of intestinal calcium absorption which are induced by corticosteroids. Corticosteroids increase the rate of tooth movement, and since new bone formation can be difficult in treated patient, they decrease the stability of tooth movement and stability of orthodontic treatment in general.
When they are used for longer periods of time, the main side effect is osteoporosis. It has been demonstrated in animals models with this type of osteoporosis that the rate of active tooth movement is greater, but tooth movement is less stable since little bone is present and no indication of bone formation. A more extensive retention may be required.
Most of these drugs used for treatment of Rheumatoid arthritis includes Immunomodulatory agents like Leflunomide, TNFantagonists like Etanercept, interleukin antagonists for example Anakinra. Immunomodulatory drugs modulates nuclear factor kappa – Beta , Tyrosine kinases in signaling pathway, interleukin – 6, MMPs and PGE2, all of which are essential for the bone remodeling process.
Patients with chronic renal failure or kidney transplants and on immunosuppressant drugs can encounter some difficulty during orthodontic treatment. Drug consumed for prevention of graft rejection (cyclosporine A) produce severe gingival hyperplasia, making orthodontic treatment, and maintenance of oral hygiene difficult. Treatment should be started or resumed after surgical removal of excessive gingival tissues once there is good oral hygiene. Whenever possible, fixed appliances should be kept to a minimum period with brackets, and avoiding the user of cemented bands. Removable appliances in these cases are not recommended, due to improper fit.
Interleukin antagonists inhibit IL–1, produced by monocytes, macrophages and some specialized cells, which are important for the inflammatory response and IL–6 and COX-2. These drugs will influence the inflammatory response following force application reducing the pace of tooth movement and bone remodeling.
TNF alpha antagonists
TNF alpha antagonist block TNF alpha in inflammatory cytokinins released by activated monocytes, macrophages and T–lymphocytes, which are essential for inflammatory responses following force application.
Cytotoxic Drugs (Chemotherapy)
These are used for the treatment of childhood cancers, there are every chances of observing disturbances in dental as well as general body growth and development, due to adverse effects of chemotherapeutic agents and radiotherapy. It is clearly stated that patients who had been on chemotherapy with Busulfan / cyclophosphamide, belongs to risk group for orthodontic treatment . These drugs are known to produce damage to precursor cells involved in bone remodeling process there by complicating tooth movement.
1. Anti Convulsants
2. Valporic acid
It has a potential to induce gingival bleeding even with minor trauma. Making orthodontic maneuvers difficult
It induces gingival hyperplasia due overgrowth of gingival collagen fibers, which involves the interdental papilla, making application of orthodontic mechanics difficult and difficulty in maintaining oral hygiene. Used during pregnancy – can produce fetal hydantion syndrome characterized by hypoplastic phalanges, cleft palate, hare lip and microcephaly
Gabapentin produce xerostomia, making oral hygiene maintenance difficult during orthodontic treatment. In these cases, clinician should be aware of possible difficulties during treatment. period, and discuss it with the patients and/ or parents and educate them so that adequate measures to maintain oral hygiene are followed.
Chronic ingestion of large amounts on daily basis may have devastating effects on a number of tissue systems, including skeletal system. Alcoholism may lead to severe complications, such as liver cirrhosis, neuropathies, osteoporosis, and spontaneous bone fractures. Circulating ethanol inhibits the hydroxylation of vitamin D3 in liver, thus impending calcium homeostasis. In such cases the synthesis of PTH is increased, tipping the balance of cellular function towards the enhanced resorption of mineralized tissues, including root resorption in order to maintain normal levels of calcium in blood. Davidovitch et al. have found that chronic alcoholics receiving orthodontic treatment are high risk of developing severe root resorption during course of orthodontic treatment.
Orthodontic have long observed that teeth move at different rates and individuals have differing response to treatment. Some of the difference are caused by change in bone remodeling induced by drugs and systemic factors. All the drugs reviewed have the therapeutic effects, as well as side effects that influences the cells targeted by orthodontic forces. There fore it is imperative that the orthodontic need to pay attention to drug consumption , history of each every patient, before and during course of orthodontic treatment. So the best treatment strategy – including force control and appointment. Intervals can be selected for each case. Acetaminophen, which does not have significant influence on the rate of tooth movement, can be recommended for controlling pain during orthodontic treatment.