BY

DR ARUN KUMAR BR
 CONTENTS
• Introduction
• Effects of drugs on induce tooth movement
• Non-steroidal anti-inflammatory drugs
• Corticosteroids
• Bisphosphonates
• Acetaminophen
• Effects of systemic factors on induced tooth movement
• Sex hormone
• Relaxin
• Thyroid hormones
• Parathyroid hormone
• Vitamin D
• Conclusion
• Bibliography
• Orthodontic tooth movement is induced by the prolonged application

of controlled forces, which create pressure and tension zones in the

PDL and alveolar bone, causing a remodeling of the sockets. This

remodeling and tooth displacement occurs by means of an

inflammatory process involving osteoclasts, osteoblast, neuropeptides,

cytokines, along with changes in innervation and local vascularization.

• Over the last few years, the discovery of new molecules and the

development of new experimental techniques have allowed orthodontic

movement to be studied at molecular levels.

• Research in molecular biology has identified the main mediators

involved in the complex process of extravasation, inflammatory cell

chemotaxis and the recruitment of osteoclast and osteoblast progenitors.

• These endogenous molecules have been found to play important roles

in the initiation, maintenance, and cessation of tooth movement.

However, some of these ligands can also cause unwanted side effects,

such as pain and root resorption. Current orthodontic research aims at

developing methods to increase the tissue concentrations of molecules

promoting tooth movement, while simultaneously decreasing the

concentration of unwanted elements, which can produce harmful side

effects.
Orthodontists often prescribe drugs to manage pain from force application
to biological tissues, manage TMJ problems, and tackle fungal and viral
infections throughout the course of treatment.
A recent review of pharmaceuticals commonly used in orthodontic practice,
provided an insight into the dosage, pharmacological actions and side
effects of these agents .
Apart from these drugs, patients who consume vitamins, minerals, and
other compounds, for the prevention or treatment of various diseases,
can also be found in every orthodontic practice. Some of these drugs
may have profound effects on the short- and long-term outcomes of
orthodontic treatment. However, in many cases little is known on the
nature of this interaction between specific drugs and orthodontic tissue
remodeling, thereby increasing the risk of negative effects.
For example, a recent editorial has raised concern regarding increased use

of methylphenidate (Ritalin), a drug used for the treatment of attention

deficit disorders in children of all ages. In these children, this drug has

apparently caused an increase in the incidence of gingival

enlargement, and a subsequent slow down of orthodontic tooth

movement .

The main objective of this presentation is to outline the mechanisms of

action and effects of some commonly used drugs on tissue remodeling

and orthodontic tooth movement.

• Effects of drugs on induce tooth movement
• Non-steroidal anti-inflammatory drugs
• Corticosteroids
• Bisphosphonates
• Acetaminophen
• Effects of systemic factors on induced tooth movement
• Sex hormone
• Relaxin
• Thyroid hormones
• Parathyroid hormone
• Vitamin D
 Generally Analgesics are divided into 2 groups
 Opioid / narcotic / morphine like analgesic
 Non- opioid / non-narcotic / antipyretic / aspirin- like analgesic or
NSAIDS

• Antipyretic-analgesic and NSAIDs are more commonly employed for

dental pain
• These Antipyretic-analgesic and NSAIDs have
 Analgesic
 Antipyretic
 Anti-inflammatory actions
 NSAIDS

Non selective Preferential COX-2

COX inhibitors inhibitors

Aspirin, Ibuprofen, Nimesulide, Meloxicam,

And Naproxen Nabumetone

Selective Analgesic- antipyretics with

COX-2 inhibitors poor anti-inflammatory action

Celecoxib, Rofecoxib, Valdecoxib, Paracetamol. (Acetaminophen)

Parecoxib And Etoricoxib.
• Non-steroidal anti-inflammatory drugs, usually abbreviated as

NSAIDs, with analgesic, antipyretic and anti-inflammatory effects - they

reduce pain, fever and inflammation. The term "non-steroidal" is used to

distinguish these drugs from steroids.

• NSAIDs are sometimes also referred to as non-steroidal anti-

inflammatory agents/analgesics (NSAIAs) or non-steroidal anti-

inflammatory medicines (NSAIMs).

• The most prominent members of this group of drugs are aspirin,

ibuprofen, and naproxen partly because they are available over-the-

counter in many areas. Paracetamol (acetaminophen) has negligible anti-

inflammatory activity, and is strictly speaking not an NSAID.

• Beginning in 1829, with the isolation of salicin from the folk remedy

willow bark, NSAIDs have become an important part of the

pharmaceutical treatment of pain (at low doses) and inflammation (at

higher doses). Part of the popularity of NSAIDs is that, unlike opioids,

they do not produce sedation or respiratory depression and have a very

low addiction rate.

• Certain NSAIDs, including ibuprofen and aspirin, have become accepted

as relatively safe and are available over-the-counter without

prescription.
• Mode of action

• Most NSAIDs act as non-selective inhibitors of the enzyme

cyclooxygenase, inhibiting both the cyclooxygenase-1 (COX-1) and

cyclooxygenase-2 (COX-2) isoenzymes. Cyclooxygenase catalyzes the

formation of prostaglandins and thromboxane from arachidonic acid

(itself derived from the cellular phospholipid bilayer by phospholipase

A2). Prostaglandins act (among other things) as messenger molecules in

the process of inflammation. This mechanism of action was elucidated

by John Vane, who later received a Nobel Prize for his work.
• Cyclooxygenase (COX) is an enzyme that is responsible for formation of

important biological mediators called prostanoids (including

prostaglandins, prostacyclin and thromboxane).

• Pharmacological inhibition of COX can provide relief from the

symptoms of inflammation and pain; this is the method of action of well-

known drugs such as aspirin and ibuprofen.

• Currently three COX isoenzymes are known—COX-1, COX-2 and COX-

3. COX-3 is a splice variant of COX-1 which retains intron one and has a

frameshift mutation, thus some prefer the name COX-1b or COX-1

variant (COX-1v).
• COX-2 inhibitors

• The discovery of COX-2 in 1991 by Daniel L. Simmons at Brigham

Young University raised the hope of developing an effective NSAID

without the gastric problems, characteristic of these agents. It was

thought that selective inhibition of COX-2 would result in anti-

inflammatory action without disrupting gastroprotective prostaglandins.

• COX-1 is a constitutively expressed enzyme with a "house-keeping" role

in regulating many normal physiological processes. One of these is in the

stomach lining, where prostaglandins serve a protective role, preventing

the stomach mucosa from being eroded by its own acid.

• When non-selective COX-1/COX-2 inhibitors (such as aspirin,

ibuprofen, and naproxen) lower stomach prostaglandin levels, these

protective effects are lost and ulcers of the stomach or duodenum and

potentially internal bleeding can result. COX-2 is an enzyme

facultatively expressed in inflammation, and inhibition of COX-2 that

produces the desirable effects of NSAIDs.

• The relatively selective COX-2 inhibiting oxicam, meloxicam, was the

first step towards developing a true COX-2 selective inhibitor. Coxibs,

the newest class of NSAIDs, can be considered as true COX-2 selective

inhibitors, and include celecoxib, rofecoxib, valdecoxib, parecoxib and

etoricoxib.
• Classical NSAIDs

• The main COX inhibitors are the non-steroidal anti-inflammatory drugs

• The classical COX inhibitors are not selective (i.e. they inhibit all types of

COX), and the main adverse effects of their use are peptic ulceration and

dyspepsia.

• It is believed that this may be due to the "dual-insult" of NSAIDs -

direct irritation of the gastric mucosa (many NSAIDs are acids), and

inhibition of prostaglandin synthesis by COX-1.

• Prostaglandins have a protective role in the gastrointestinal tract,

preventing acid-insult to the mucosa.

• Newer NSAIDs

• Selectivity for COX-2 is the main feature of celecoxib, rofecoxib and other
members of this drug class, but these drugs carry the risk of peptic
ulceration.

• COX-2-selectivity does not seem to affect other side-effects of NSAIDs

(most notably an increased risk of renal failure), and some results have
aroused the suspicion that there might be an increase in the risk for heart
attack, thrombosis and stroke by a relative increase in thromboxane.

• Rofecoxib was taken off the market in 2004 because of these concerns.

• Some other COX-2 selective NSAIDs, such as celecoxib and etoricoxib,

are still on the market.
• Non-NSAID COX inhibition

• It has been suggested that acetaminophen, also known as paracetamol,

reversibly inhibits COX-3, although there is now some doubt about this

theory. COX-3 produces prostanoids in the brain, but does not

participate in eicosanoid signalling in inflammation. Acetaminophen

thereby may interfere with the perception of pain. Since it has no effect

on inflammation, it is not classed as an NSAID.

• Cardiovascular side effects of COX inhibitors

• COX-2 inhibitors have been found to increase the risk of atherothrombosis even

with short term use. A 2006 analysis of 138 randomised trials and almost 150 000

participants showed that selective COX-2 inhibitors are associated with a

moderately increased risk of vascular events, mainly due to a twofold increased risk

of myocardial infarction, and also that high dose regimens of some traditional

NSAIDs such as diclofenac and ibuprofen are associated with a similar increase in

risk of vascular events.

 Non-steroidal anti-inflammatory and
antipyretic- analgesic drugs
 Non selective COX inhibitors (conventional NSAIDS)
 Salicylates: Aspirin
 Propionic acid derivative: Ibuprofen, Naproxen, Ketoprofen, Flubiprofen.
 Anthranilic acid derivative: Mephenamic acid
 Aryl-acetic acid derivative: Diclofenac
 Oxicam derivative: Piroxicam, Tenoxicam.
 Pyrrolo-pyrrole derivative: Ketorolac
 Indole derivative: Indomethacin
 Pyrazolone derivative: Phenylbutazone, Oxyphenbutazone.
 Preferential COX-2 inhibitors

Nimesulide, Meloxicam, Nabumetone

 Selective COX-2 inhibitors

Celecoxib, Rofecoxib, Valecoxib, Etoricoxib

 Analgesic- antipyretics with poor anti-inflammatory action

 Para-aminophenol derivative: Paracetamol. (Acetaminophen)

 Pyrazolone derivative: Metamizol (Dipyrone), Propiphenaqzone.

 Benzoxazocine derivative: Nefopam.

 Non-steroidal anti-inflammatory drugs

• These are most commonly used in orthodontics for the control of pain

following mechanical force application to teeth.

• In 1971, Vane and Coworkers made the landmark observation that

aspirin and some NSAIDs block PG (prostaglandin) generation, which is

now considered to be the major mechanism of action of NSAIDs.

• Prostaglandins, postacyclin (PGI2), and thromboxane (TXA2) are

produced from AA by enzyme cyclooxygenase (COX-1 & COX-2)

isoforms
• COX-1  serves as physiological house keeping function

(secretion of mucus for protection of gastric mucosa, homeostasis

and maintenance of renal )

• COX-2  present in minute quanties which is induced by

cytokines & other signal molecules at the site of inflammation 

generation of PGs locally which mediate many of the

inflammatory changes. [certain sites in brain & kidney

(Juxtaglomerular cells) which may serve as physiological role]

• Most NSAIDs inhibit COX-1 & COX-2 non-selectively, but now some

selective COX-2 inhibitors have been produced.

• Aspirin acetylates COX at a serine residue and causes irreversible

inhibition, while other NSAIDs are competitive and reversible

inhibitors.
 Aspirin

• Is acetylsalicylic acid
• One of oldest analgesic - antiinflammatory drug and still used widely
• Rapidly converted in the body to salicylic acid which is responsible for
most of the actions
• Pharmacological action
• Analgesic ,antipyretic, antiinflammatory actions
• Metabolic effects
• Respiration
• Acid base and electrolyte balance
• CVS
• GIT
• Urate excretion
• Blood
• Analgesic action:

• Aspirin and other NSAIDs ↓↓ dull aching pain of low intensity (tooth
ache and head ache)

• They act by ↑↑ the pain threshold in the brain

• They are not effective in visceral and ischemic pain of high

intensities
• Antipyretic action:
• Brings down body temperature in patients with fever

• They act by resetting the thermostatic mechanism in the thalamus

• Also causes ↑↑ heat loss by cutaneous vasodilatation & ↑↑ sweating

• Anti- inflammatory action:

• Reduces signs of inflammation like pain, tenderness, swelling, vasodilatation

and leucocyte infiltration are suppressed

• By inhibiting the synthesis of PGs they inhibit inflammation

• Respiration:

• Salicylates in therapeutic doses ↑↑ the rate and depth of respiration

• They inhibit respiration in toxic doses

• Acid-base and electrolyte balance
• A person on Salicylates is more prone for acid base imbalance
• Causes hyperventilation ∴ co2 is washed out leading to respiratory
alkalosis
• In order to ↓↓ alkali level, kidneys wash out HCO3Inform of
potassium or sodium bicarbonates called as compensated respiratory
alkalosis
• When higher doses of aspirin are administered there is respiratory
depression and there is retention of Co2  respiratory acidosis
• Blood:
• They inhibit platelet aggregation in low doses by inhibiting the
synthesis of thromboxane A2 (this effect last for about a week)
• On prolonged administration the bleeding time is prolonged (inhibit
Vit K dependant clotting factors)
• On GIT:
• Aspirin + released salicylic acid  irritate gastric mucosa epigastric distress,
nausea & vomiting
• Also stimulates CTZ (chemoreceptor trigger zone)
• PGE2 has a cytoprotective action on gastric mucosa
• NSAIDs by inhibiting PGs may cause gastric and peptic ulceration
On CVS:
Aspirin has no direct effect in therapeutic doses
↑↑ dosage  ↑ cardiac output to meet ↑ peripheral O2 demand & cause
direct VD
Toxic dose  depress Vasomotor centre (BP may fall)
On Metabolic action:
Aspirin causes uncoupling of oxidative phosphorylation especially in
skeletal muscles leading to ↑ heat production
↓blood sugar level especially in diabetics and ↑ blood sugar level in toxic
dose
Low dose cause retention of uric acid (<2g/day) & high dose cause excretion of uric
acid (>5 g/day)
• Adverse effect: • Uses:
• Nausea • Analgesic, antipyretic
• Epigastric distress & antiinflammatory
• Gastritis • Headache, toothache
• Dysmennhorrea
• Peptic ulcer
• Myalgia
• Haemorrhage
• Low dose aspirin is
• Perforation given after MI to
• Depress of respiration prevent reinfarction
• Intolerance • Pregnancy induced
• Salicylism hypertension
• Acute salicylate
intoxication
• Precaution and contraindication
• In bleeding disorders

• Children suffering from chicken pox/influenza

• Chronic liver disease

• Avoided in diabetics, in those with low cardiac reserve or frank CHF and in juvenile
rheumatoid arthritis

• It should be stopped 1week before elective surgery, dental extraction

• If given during pregnancy may be responsible for low birth babies, delayed
labour, greater postpartum bleeding and premature closure of ductus arterious are
possible if aspirin is taken at or near term

• Should be avoided in breast feeding mothers

• Avoid high dose in G-6-PD deficient individuals –haemolysis can occur

 Propionic acid derivatives
• Ibuprofen
• 1st member introduced in 1969 as a better tolerated alternative to
aspirin
• Have similar pharmacodynamic properties, but differ considerably in
potency & some extent of duration of action
• Antiinflammatory efficacy is rated somewhat lower than high dose of
aspirin
• All inhibit PG synthesis
• Adverse effect:
• Ibuprofen & all its congeners are better tolerated than aspirin and
side effects are milder and their incidence is lower.
• Gastric discomfort , nausea, vomiting
• CNS  headache, dizziness, blurring of vision, tinnitus &
depression
• Rashes, itching and other hypersensitivity phenomena are
infrequent
• They are not to be prescribed to pregnant women and should be
avoided in peptic ulcer patient
• Uses:
• Used as a simple analgesic & antipyretic in the same way as low

dose of aspirin

• Ibuprofen & its congeners are widely used in rheumatoid arthritis,

osteoarthritis and other musculoskeletal disorders, especially

where pain is more prominent than inflammation

• Indicated in soft tissue injuries, tooth extraction, fractures,

vasectomy, postpartum and postoperatively: suppress swelling

and inflammation and are very popular in dentistry

 Anthranilic acid derivative
• Mephenamic acid:
• Has analgesic, antipyretic & antiinflammatory action , which inhibits
COX as well as antagonises certain actions of PGs
• It exerts peripheral as well as central analgesic action
• Adverse effect:
• Diarrhoea (dose related side effect)
• Epigastric distress
• Haemolytic anaemia is rare but serious complication
• Uses:
• Indicated primarily as analgesic in muscle, joint and soft tissue pain
where strong antiinflammatory is not required
• Quite effective in dysmenorrhoea
• Useful in some case of rheumatoid and osteoarthritis but has no
distinct advantage
 Aryl acetic acid derivative
• Diclofenac sodium:
• Analgesic, anti-pyretic & antiinflammatory action
• Inhibits PG synthesis & has short lasting antiplatelet action
• Neutrophil & superoxide production at the inflammatory site are reduced
• Well absorbed orally
• Because of good tissue, concentration in joints and other site of inflammation
is maintained for longer period extending the therapeutic effect
• Adverse effect:
• Mild epigastric pain, nausea, headache, dizziness, rashes
• Gastric ulceration & bleeding are less common
• Diclofenac is most extensively used NSAID:
• Rheumatoid & osteoarthritis, toothache, bursitis, ankylosis spondylitis,
• Dysmenorrhoea, pre & post-traumatic inflammatory condition – afford
quick relief of pain and wound.
 Oxicam Derivatives
• Is long acting NSAIDs with good antiinflammatory & analgesic-antipyretic
actions
• It is a reversible inhibitor of COX
• It is rapidly & completely absorbed
• Single daily administration is sufficient
• Adverse effect:
• Heart burn, nausea, anorexia
• It is better tolerated & less uclerogenic than indomethacin or
phenylbutazone
• Causes less faecal blood loss than aspirin
• Edema and reversible azotaemia have been seen in some cases
• Uses:
• Used as short term analgesic as well as long term antiinflammatory in
rheumatoid and osteoarthritis, ankylosing spondylitis, acute gout,
musculoskeletal injuries and in dentistry
 Pyrrolo-pyrrole derivatives
• Ketorolac:
• Potent analgesic & modest antiinflammatory action
• In post operative pain it has equaled the efficacy of morphine, but
does not interact with opioid receptors and free of opioid side effects
• It inhibits PG synthesis and relieves pain by a peripheral mechanism
• In short lasting pain it has compared favourably with aspirin
• Rapidly absorbed after oral and im administration
• Adverse effect:
• Nausea, abdominal pain, dyspepsia, ulceration, loose stools,
drowsiness, headache, dizziness, nervousness, pruritus, pain at
injection site, rise in serum tranaminase & fluid retention has been
noted.
• Uses:
• Postoperative, dental and acute musculoskeletal pain
• Also used for renal colic, migraine & pain due to bony metastasis
 Indole Derivative
• Indomethacin:
• It is a potent antiinflammatory drug with prompt antipyretic action
• It relieves only antiinflammatory or tissue injury related pain
• Potent inhibitor of PG synthesis & suppresses neutrophil molility
• In toxic doses it uncouples oxidative phosphorylation
• Well absorbed orally
• Adverse effect:
• High incidence of gastrointestinal & CNS side effects is produced
• Gastric irritation, nausea, anorexia, gastric bleeding and diarrhoea are
common
• Frontal headache, mental confusion, dizziness, ataxia, hallucination,
depression can occur
• Leukopenia, rashes, other hypersensitivity reaction are reported
• Increased risk of bleeding due to decreased platelet aggregability
• Contraindicated in machinery operators, drivers, psychiatric patients,
epileptics, kidney disease, pregnant women and children
• Uses:

• Because of prominent adverse effects, it is used as a reserve drug in

conditions requiring potent antiinflammatory action like ankylosing

spondylitis, acute exacerbations of destructive arthopathies, psoriatic

arthritis and acute gout that are not resopnding to NSAIDs

• Malignancy associated fever refractory to other antipyretics may respond to

indomethacin

• Has been most common drug for medical closure of patent ductus

arteriosus, Bartter’s syndrome responds dramatically.

 COX-2 inhibitors
• Nimesulide:
• Is weak inhibitor of PG synthesis
• Analgesic, antiinflammatory, antipyretic action of this drug has been rated
comparable to other NSAIDs
• Primarily used for short lasting painful inflammatory condition like sports
injuries, sinusitis, ENT disorders, dental surgery, low backache,
dysmenorrhoea, postoperative pain, osteoarthritis & fever
• Completely absorbed orally
• Adverse effect:
• GIT epigastralgia, nausea, heart burn, loose motions
• Dermatological rash, purities
• CNS dizziness, somnolence
Recent studies has shown several instances of hepatic failures & withdrawn in
most of the countries.
• Meloxicam:

• Newer congener of piroxicam has aCOX-2:COX 1 selectivity ratio of about 10

• Efficacy of meloxicam in oseto & rheumatoid arthritis is comparable to

piroxicam

• In short term studies , gastric changes with the lower doses were found to be

similar to placebo, but at the higher dose they were intermediate b/w

placebo & piroxicam

• Gastric side effect are milder, but ulcer complications (bleeding ,perforation)

are reported on long term use.

• Selective COX-2 inhibitors
• Advantage of inhibiting COX-2 without affecting COX-1 function,
some highly selective COX-2 inhibitors have been introduced over
past decade.
• COX-2 inhibitors cause little gastric mucosal damage, occurrence of
peptic ulcer and ulcer bleeding are lower than that of NSAIDs
• Do not depress TXA2 production by platelet aggregation or prolong
bleeding time, but may reduce PGI2 production by vascular
endothelium
• Celecoxib:
• Has antiinflammatory, analgesic & antipyretic actions with low
ulcerogenic potential
• Tolerability of celecoxib is better than older NSAIDs
• Slowly absorbed
• Abdominal pain, dyspepsia & mild diarrhoea are common side
effect
• Rofecoxib

• Highly selective COX-2 inhibitor introduced in 1999 had become

popular osteo & rheumatoid arthritis as well as for dental, post

operative and acute musculosketal pain

• This drug was withdrawn worldwide by its manufacturer in

September 2004 due high incidence of myocardial infraction and

strokes

• Banned in India
• Valecoxib

• Have similar efficacy and tolerability as earlier COX-2 inhibitors

• Used in osteo & rheumatoid arthritis, dental, postoperative pain,

dysmenorrhoea

• Severe skin reaction such as Steven Johnson syndrome has reported

• Etoricoxib

• Highly selective COX-2 inhibitors suitable for once a day treatment of

osteo & rheumatoid arthritis, acute gouty arthritis dental,

postoperative pain, dysmenorrhoea without affecting the platelet
function or damging gastric mucosa
 Para amino derivatives
• Paracetamol (Acetaminophen)
• History
• In ancient and medieval times, known antipyretic agents were
compounds contained in white willow bark (a family of chemicals
known as salicins, which led to the development of aspirin), and
compounds contained in cinchona bark.

• Cinchona bark was also used to create the anti-malaria drug quinine.
Quinine itself also has antipyretic effects. Efforts to refine and isolate
salicin and salicylic acid took place throughout the middle- and late-19th
century, and was accomplished by Bayer chemist Felix Hoffmann (this
was also done by French chemist Charles Frédéric Gerhardt 40 years
earlier, but he abandoned the work after deciding it was impractical).
• When the cinchona tree became scarce in the 1880s, people began to look

for alternatives. Two alternative antipyretic agents were developed in

the 1880s: Acetanilide in 1886 and Phenacetin in 1887.

• Harmon Northrop Morse first synthesized paracetamol via the reduction

of p-nitrophenol with tin in glacial acetic acid in 1878; however,

paracetamol was not used in medical treatment for another 15 years.

• In 1893, paracetamol was discovered in the urine of individuals that had

taken phenacetin, and was concentrated into a white, crystalline

compound with a bitter taste. In 1899, paracetamol was found to be a

metabolite of acetanilide. This discovery was largely ignored at the time.

• In 1946, the Institute for the Study of Analgesic and Sedative Drugs
awarded a grant to the New York City Department of Health to study
the problems associated with analgesic agents. Bernard Brodie and Julius
Axelrod were assigned to investigate why non-aspirin agents were
associated with the development of methemoglobinemia, a condition
that decreases the oxygen-carrying capacity of blood and is potentially
lethal.
• In 1948, Brodie and Axelrod linked the use of acetanilide with
methemoglobinemia and determined that the analgesic effect of
acetanilide was due to its active metabolite paracetamol. They advocated
the use of paracetamol, since it did not have the toxic effects of
acetanilide.
• The product was first sold in 1955 by McNeil Laboratories as a pain and
fever reliever for children, under the brand name Tylenol Children's
Elixir.
• In 1956, 500 mg tablets of paracetamol went on sale in the United

Kingdom under the trade name Panadol, produced by Frederick Stearns

& Co, a subsidiary of Sterling Drug Inc. Panadol was originally available

only by prescription, for the relief of pain and fever, and was advertised

as being "gentle to the stomach," since other analgesic agents of the time

contained aspirin, a known stomach irritant. In June 1958, a children's

formulation, Panadol Elixir, was released.

• In 1963, paracetamol was added to the British Pharmacopoeia, and has

gained popularity since then as an analgesic agent with few side-effects

and little interaction with other pharmaceutical agents.

• Mechanism of action
• The mechanism by which paracetamol reduces fever and pain is still a
source of considerable debate.
• The reason for this confusion has largely been due to the fact that
paracetamol reduces the production of prostaglandins, pro-
inflammatory chemicals the production of which is also inhibited by
aspirin, but, unlike aspirin, paracetamol does not have much anti-
inflammatory action.
• Likewise, whereas aspirin inhibits the production of the pro-clotting
chemicals thromboxanes, paracetamol does not.
• Aspirin is known to inhibit the cyclooxygenase (COX) family of
enzymes, and, because of paracetamol's partial similarity of aspirin's
action, much research has focused on whether paracetamol also inhibits
COX.
• Metabolism

• Paracetamol is metabolised primarily in the liver, where its major

metabolites include inactive sulfate and glucuronide conjugates, which

are excreted by the kidneys.

• Only a small, yet significant amount is metabolised via the hepatic

cytochrome P450 enzyme system (its CYP2E1 and CYP1A2 isoenzymes),

which is responsible for the toxic effects of paracetamol due to a minor

alkylating metabolite (N-acetyl-p-benzo-quinone imine, abbreviated as

NAPQI).
• Adverse effects

• In recommended doses, paracetamol does not irritate the lining of the

stomach, affect blood coagulation as much as NSAIDs, or affect function of

the kidneys. However, some studies have shown that high dose-usage

(greater than 2000 mg per day) does increase the risk of upper

gastrointestinal complications.

• Paracetamol is safe in pregnancy, and does not affect the closure of the fetal

ductus arteriosus as NSAIDs can. Unlike aspirin, it is safe in children, as

paracetamol is not associated with a risk of Reye's syndrome in children

with viral illnesses.

• Like NSAIDs and unlike opioid analgesics, paracetamol has not been found

to cause euphoria or alter mood in any way. Paracetamol and NSAIDs have

the benefit of bearing a low risk of addiction, dependence, tolerance, and

withdrawal, but, unlike opioid medications, may damage the liver; however,

this is in general, taken into account when compared to the danger of

addiction.

• Paracetamol, particularly in combination with weak opioids, is more likely

than NSAIDs to cause rebound headache (medication overuse headache),

although less of a risk than ergotamine or triptans used for migraines.

• The toxic dose of paracetamol is highly variable.

• In adults, single doses above 10 grams or 150 mg/kg have a reasonable

likelihood of causing toxicity. Toxicity can also occur when multiple smaller

doses within 24 hours exceeds these levels, or even with chronic ingestion of

doses as low as 4 g/day, and death with as little as 6 g/day.

• In children, acute doses above 200 mg/kg could potentially cause toxicity.

This higher threshold is largely due to larger kidneys and livers relative to

body size in children versus adults, and hence greater tolerance of

paracetamol overdose than adults.

• Acute paracetamol overdose in children rarely causes illness or death.

• In a normal dose of 1 gram of acetaminophen four times a day, one-third

of patients may have an increase in their liver function tests to three

times the normal value. However, it is unclear as to whether this leads to

liver failure.
 Adverse Reactions

• Serious Reactions • Common Reactions

• Hepatotoxicity • Nausea
• Cholestatic jaundice • Urticaria
• Hepatic necrosis • Rash
• Renal tubular necrosis, acute
• Analgesic nephropathy, chronic
• Anemia, hemolytic
• Pancytopenia
• Thrombocytopenia
• Leukopenia
• Neutropenia
• Hypersensitivity rxn
• Angioedema (rare)
• Anaphylaxis (rare)
• Acetaminophen (paracetamol), a weak COX 1 & 2 inhibitor that also

reduces urinary PG levels after systemic adminsitration, has shown no

effect on orthodontic tooth movement in guinea pigs and rabbits.

• Comparative studies & clinical experience have demonstrated that

acetaminophen is effective for controlling pain & discomfort associated

with orthodontic treatment

• Since NSAIDs are freely available over the counter, patients should be

advised not to take these drugs during orthodontic treatment, without

the orthodontists knowledge. One drug of choice for the patients under

orthodontic treatment is acetaminophen , whose mode of action is

central rather than peripheral

 Uses
• NSAIDs are usually indicated for the treatment of acute or chronic conditions where
pain and inflammation are present.
• NSAIDs are generally indicated for the symptomatic relief of the following
conditions: (Rossi, 2006)
• Rheumatoid arthritis
• Osteoarthritis
• Inflammatory arthropathies (e.g. ankylosing spondylitis, psoriatic arthritis, Reiter's
syndrome)
• Acute gout
• Dysmenorrhoea
• Metastatic bone pain
• Headache and migraine
• Postoperative pain
• Mild-to-moderate pain due to inflammation and tissue injury
• Pyrexia
• Renal colic
• They are also given to just born infants whose ductus arteriosus is not closed within
24 hours of birth
• Aspirin, the only NSAID able to irreversibly inhibit COX-1, is also indicated for
inhibition of platelet aggregation.; an indication useful in the management of
arterial thrombosis and prevention of adverse cardiovascular events. It shows
inhibition of platelet aggregation because it inhibits the action of thromboxane -A.
• Pharmacokinetics
• Most NSAIDs are weak acids, with a pKa of 3-5.
• They are absorbed well from the stomach and intestinal mucosa.
• They are highly protein-bound in plasma (typically >95%), usually to
albumin, so that their volume of distribution typically approximates to
plasma volume.
• Most NSAIDs are metabolized in the liver by oxidation and conjugation to
inactive metabolites which are typically excreted in the urine, although some
drugs are partially excreted in bile.
• Metabolism may be abnormal in certain disease states, and accumulation
may occur even with normal dosage.

• Ibuprofen and diclofenac have short half-lives (2-3 hours).

• Some NSAIDs (typically oxicams) have very long half-lives (e.g. 20-60
hours).
• Adverse effects

• The widespread use of NSAIDs has meant that the adverse effects of

these relatively safe drugs have become increasingly prevalent.

• The two main adverse drug reactions (ADRs) associated with

NSAIDs relate to gastrointestinal (GI) effects and renal effects of the

agents.

• These effects are dose-dependent, and in many cases, severe enough

to pose the risk of ulcer perforation, upper gastrointestinal bleeding,

and death, limiting the use of NSAID therapy.

• An estimated 10-20% of NSAID patients experience dyspepsia.

• Gastrointestinal ADRs
• The main ADRs associated with use of NSAIDs relate to direct and indirect
irritation of the gastrointestinal tract (GIT). NSAIDs cause a dual insult on the
GIT - the acidic molecules directly irritate the gastric mucosa; and inhibition of
COX-1 reduces the levels of protective prostaglandins.

• Common gastrointestinal ADRs include: (Rossi, 2006)

• Nausea/Vomiting
• Dyspepsia
• Gastric ulceration/bleeding
• Diarrhoea
• There are also some differences in the propensity of individual agents to cause
gastrointestinal ADRs.

• Indomethacin, ketoprofen and piroxicam appear to have the highest prevalence

of gastric ADRs, while ibuprofen (lower doses) and diclofenac appear to have
lower rates. (Rossi, 2006)
• Certain NSAIDs, such as aspirin, have been marketed in enteric-coated
formulations which are claimed to reduce the incidence of
gastrointestinal ADRs. Similarly, there is a belief that rectal formulations
may reduce gastrointestinal ADRs. However, in consideration of the
mechanism of such ADRs and indeed in clinical practice, these
formulations have not been shown to have a reduced risk of GI
ulceration. (Rossi, 2006)

• Commonly, gastrointestinal adverse effects can be reduced through

suppressing acid production, by concomitant use of a proton pump
inhibitor, e.g. omeprazole; or the prostaglandin analogue misoprostol.
Misoprostol is itself associated with a high incidence of gastrointestinal
ADRs (diarrhoea). While these techniques may be effective, they prove
to be expensive for maintenance therapy.
• Renal ADRs

• NSAIDs are also associated with a relatively high incidence of renal

ADRs. The mechanism of these renal ADRs is due to changes in renal

haemodynamics (blood flow), ordinarily mediated by prostaglandins,

which are affected by NSAIDs.

• Prostaglandins normally cause vasodilation of the afferent arterioles of

the glomeruli. This helps maintain normal glomerular perfusion and

glomerular filtration rate (GFR), an indicator of renal function. By

blocking this prostaglandin-mediated effect, NSAIDs ultimately may

cause renal impairment.

• Common ADRs associated with altered renal function include: (Rossi,
2006)
• Salt and fluid retention
• Hypertension
• These agents may also cause renal impairment, especially in
combination with other nephrotoxic agents.
• Renal failure is especially a risk if the patient is also concomitantly
taking an ACE inhibitor and a diuretic - the so-called "triple whammy"
effect. (Thomas, 2000)
• In rarer instances NSAIDs may also cause more severe renal conditions:
(Rossi, 2006)
• Interstitial nephritis
• Nephrotic syndrome
• Acute renal failure
• Acute tubular necrosis
• Photosensitivity
• Photosensitivity is a commonly overlooked adverse effect of many of the
NSAIDs. (Moore, 2002)
• It is somewhat ironic that these anti-inflammatory agents may
themselves produce inflammation in combination with exposure to
sunlight.
• The 2-arylpropionic acids have proven to be the most likely to produce
photosensitivity reactions, but other NSAIDs have also been implicated
including piroxicam, diclofenac and benzydamine.
• The mechanism of photosensitivity, responsible for the high
photoactivity of the 2-arylpropionic acids, is the ready decarboxylation
of the carboxylic acid moiety. The specific absorbance characteristics of
the different chromophoric 2-aryl constituents, affects the
decarboxylation mechanism.
• While ibuprofen is somewhat of an exception, having weak absorption,
it has been reported to be a weak photosensitizing agent.
• Combinational risk
• If a COX-2 inhibitor is taken, one should not use a traditional NSAID
(prescription or over-the-counter) concomitantly.
• In addition, patients on daily aspirin therapy (as for reducing
cardiovascular risk or colon cancer risk) need to be careful if they also
use other NSAIDs, as the latter may block the cardioprotective effects of
aspirin.
• Cardiovascular risk
• A recent meta-analysis of all trials comparing NSAIDs found an 80%
increase in the risk of myocardial infarction with both newer COX-2
antagonists and high dose traditional anti-inflammatory compared with
placebo (Kearney et al, BMJ 2006;332:1302-1308).
• NSAIDs double the risk of development of symptomatic heart failure in
patients without a history of cardiac disease. In patients with such a
history, however, use of NSAIDs may lead to a more than 10-fold
increase in heart failure . Overall, NSAIDs are estimated to be
responsible for up to 20 percent of hospital admissions for congestive
heart failure
• During pregnancy
• NSAIDs are not recommended during pregnancy, particularly
during the third trimester. While NSAIDs as a class are not direct
teratogens, they may cause premature closure of the fetal ductus
arteriosus and renal ADRs in the fetus. Additionally, they are linked
with premature birth (Ostensen & Skomsvoll, 2004).

• Aspirin, however, is used together with heparin in pregnant women

with antiphospholipid antibodies (Cervera & Balasch, 2004).

• In contrast, paracetamol (acetaminophen) is regarded as being safe

and well-tolerated during pregnancy (Graham et al., 2005). Doses
should be taken as prescribed, due to risk of hepatotoxicity with
overdoses (Wilkes et al, 2005).
• Other ADRs

• Common ADRs, other than listed above, include: raised liver enzymes,
headache, dizziness (Rossi, 2006).

• Uncommon ADRs include: hyperkalaemia, confusion, bronchospasm, rash

(Rossi, 2006). Ibuprofen may also rarely cause irritable bowel syndrome
symptoms.

• Most NSAIDs penetrate poorly into the central nervous system (CNS).
However, the COX enzymes are expressed constitutively in some areas of
the CNS, meaning that even limited penetration may cause adverse effects
such as somnolence and dizziness.
 Analgesic /NSAIDs in Dentistry
• Are mainstay for management of acute dental pain.
• Mild-moderate pain with little inflammation  paracetamol or low dose
ibuprofen
• Postextraction or acute but short lasting ketorolac, diclofenac, nimesulide/
aspirin
• Patients with H/O asthma or anaphylatoid reaction to aspirin/ other NSAIDs
nimesulide
• Paediatric patients only paracetamol, aspirin, ibuprofen & naproxen have been
adequately evaluated in children. Due to risk of Reye’s syndrome, aspirin
should be avoided unless viral infection can be ruled out.
• Pregnancy paracetamol is safest & low dose of aspirin is second best
• Hypertensive, epileptic, diabetic, ischaemic heart disease and patient on other
drugs for long term regularly should be considered for drug interaction with
NSAIDs and should consult physician.
• Harell and colleagues in 1977, observed the synthesis of PG from

osteoclast-like cell cultured on orthodontic screws, which had been

cemented to the bases of petri dishes.

• In 1980, Yamasaki and colleagues found that Indomethacin, non-steroidal

COX1 & COX2 inhibitor, reduced bone resorption and orthodontic tooth

movement in rats.

• These authors also demonstrated that the local injection of PG E-1 &E-2

into the submucosa overlying orthodontically treated doubled the rate of

the tooth movement, both in monkeys and humans

• Because PGs appear to be important in the process of tooth movement, it

has been suggested that the use of over the counter NSAIDs by

orthodontic patients can significantly alter the efficacy of tooth

movement

• Recently Jerome and colleagues showed that Celebrex administered in rats

during the application of forces did not interfere with the tooth

movement and appeared to offer some protection against root resportion

but additional research needed to analyze the effects of this in human

orthodontic patients.
• Fewer osteoclasts were observed in the pressure side of orthodontically
moved incisors in rats treated with aspirin / ibuprofen. This may be due
to inhibition of PGs , there by reduced bone resportion and teeth moved
less. When PGs injected in the pressure area there was increased tooth
movement noticed. (Yamasaki et al)
• Lee introduced PGs locally and systemically in guinea pigs and observed
a significant in no. of osteoclasts in the pressure side of orthodontic tooth
movement.
• Study by Davidovitch and Shanfeld with cats showed that PGs were
responsible for bone resorption during tooth movement.
• Ibuprofen and aspirin significantly reduced the no. of resorption
lacunae and osteoclasts in the pressure areas of orthodontic tooth
movement, whereas Acetaminophen did not reduce no. of resorption
lacunae and osteoclasts in the pressure areas of orthodontic tooth
movement.
• Acetaminophen probably does not alter osseous regeneration or dental
movement because it acts at CNS level and does not affect the peripheral
secretion of PGs.
 Corticosteroids

• are a class of steroid hormones that are produced in the adrenal cortex.

• Corticosteroids are involved in a wide range of physiologic systems such

as stress response, immune response and regulation of inflammation,
carbohydrate metabolism, protein catabolism, blood electrolyte levels,
and behavior.

• Glucocorticoids such as cortisol control carbohydrate, fat and

protein metabolism and are anti-inflammatory by preventing
phospholipid release, decreasing eosinophil action and a number of
other mechanisms.

• Mineralocorticoids such as aldosterone control electrolyte and water

levels, mainly by promoting sodium retention in the kidney.
• Synthetic drugs with corticosteroid-like effect are used in a variety of
conditions, ranging from brain tumors to skin diseases.
• Dexamethasone and its derivatives are almost pure glucocorticoids,
while prednisone and its derivatives have some mineralocorticoid action
in addition to the glucocorticoid effect.
• Hydrocortisone (cortisol) is available for replacement therapy, e.g. in
adrenal insufficiency and congenital adrenal hyperplasia.
• Synthetic glucocorticoids are used in the treatment of joint pain or
inflammation (arthritis), temporal arteritis, dermatitis, allergic reactions,
asthma, hepatitis, systemic lupus erythematosus, inflammatory bowel
disease (ulcerative colitis and Crohn's disease), sarcoidosis and for
glucocorticoid replacement in Addison's disease or other forms of
adrenal insufficiency.
• Topical formulations for treatment of skin, eye diseases (uveitis) or
inflammatory bowel disease are available.
• Corticosteroids are also used supportively to prevent nausea, often in
combination with 5-HT3 antagonists
• Typical undesired effects of glucocorticoids present quite uniformly as

drug-induced Cushing's syndrome.

• Typical mineralocorticoid side effects are hypertension (abnormally high

blood pressure), hypokalemia (low potassium levels in the blood),

hypernatremia (high sodium levels in the blood) without causing

peripheral edema, metabolic alkalosis and connective tissue weakness

(Werner, 2005).

• Clinical and experimental evidence indicates that corticosteroids can

cause permanent eye damage by inducing central serous retinopathy

• In 2004, Kalia and colleagues evaluated the rate of tooth movement in rats
during short and long term corticosteroid therapy and demonstrated
that bone remodeling seemed to slow in acute administrations, whereas
the rate of tooth movement increased in chronic treatment.
• Clinically , these results suggest that it is possible to treat patients
undergoing corticosteroid therapy with minimum adverse effects.
• Patient who are within
• the short term phase of drug use may be advised to postpone
orthodontic treatment or , because their bone turnover will be
delayed, should be scheduled for appliance adjustments at longer
intervals
• In long term drug therapy , when the rate of tooth movement might
be accelerated, orthodontic appliances should be adjusted as usual or
even more frequently.
 Bisphosphonate
• In pharmacology, bisphosphonates (also called: diphosphonates) is a
class of drugs that inhibits osteoclast action and the resorption of bone.
Its uses include the prevention and treatment of osteoporosis, osteitis
deformans ("Paget's disease of bone"), bone metastasis (with or without
hypercalcemia), multiple myeloma and other conditions that feature
bone fragility.
History
• Bisphosphonates were developed in the 19th century, but were first
investigated in the 1960s for use in disorders of bone metabolism.
• Their non-medical use included water softening in irrigation systems
used in orange groves.
• The initial rationale for their use in humans was their potential in
preventing the dissolution of hydroxylapatite, the principal bone
mineral, and hence arresting bone loss.
• Only in the 1990s was their actual mechanism of action demonstrated
Pharmacokinetics

• Oral or iv ,about 50% is excreted unchanged by the kidney. The

remainder has a very high affinity for bone tissue, and is rapidly

absorbed onto the bone surface.

Mechanism of action

• Bisphosphonates, when attached to bone tissue, are "ingested" by

osteoclasts, the bone cell that breaks down bone tissue.

• There are two classes of bisphosphonate: the N-containing and Non-N-

containing bisphosphonates. The two types of bisphosphonates work

differently in killing osteoclast cells.

• Uses

• Bisphosphonates are used clinically for the treatment of osteoporosis,

osteitis deformans (Paget's disease of the bone), bone metastasis (with or
without hypercalcemia), multiple myeloma and other conditions that
feature bone fragility.

• High-potency intravenous bisphosphonates have shown to modify

progression of skeletal metastasis in several forms of cancer, especially
breast cancer.

• Other bisphosphonates, medronate (R1, R2 = H) and oxidronate (R1 = H,

R2 = OH) are mixed with radioactive technetium and are injected for
imaging bone and detecting bone disease.

• More recently, bisphosphonates have been used to reduce fracture rates

in children with osteogenesis imperfecta.
• Side-effects

• Oral bisphosphonates can give stomach upset and inflammation and

erosions of the esophagus, which is the main problem of oral N-
containing preparations. This can be prevented by remaining seated
upright for 30 to 60 minutes after taking the medication.

• Intravenous bisphosphonates can give fever and flu-like symptoms after

the first infusion. Notably, these symptoms do not recur with
subsequent infusions.

• There is a slightly increased risk for electrolyte disturbances, but not

enough to warrant regular monitoring.

• In chronic renal failure, the drugs are excreted much slower, and dose
adjustment is required.
• Bisphosphonates have been associated with osteonecrosis of the jaw;

with the mandible twice as frequently affected as the maxilla and most

cases occurring following high-dose intravenous administration used for

some cancer patients. Some 60% of cases are preceded by a dental

surgical procedure and it has been suggested that bisphosphonate

treatment should be postponed until after any dental work to eliminate

potential sites of infection.

• A number of cases of severe bone, joint, or musculoskeletal pain have

been reported, prompting labeling changes

 Clodronate
• Is Non-N-containing bisphosphonates ,and less potent than N-
containing bisphosphonate (Fleisch,2000)
• is an anti resorptive agent, widely used in treatment of metabolic bone
disease (Plosker and Goa, 1994) and can considered a potential anti
inflammatory drug.
• It has been shown to suppress signs of inflammation in arthritic rats (Osterman
et al 1995 ; Richards et al 2001) and to relieve bone pain in patient with
metastatic prostate cancer (Elomaa et al)
• It also shown to inhibit the production of pro -inflammatory molecules such as
IL-1beta, IL-6, TNF-alpha, nitric oxide and PGE2 in macrophages and or
osteoblastic cells
• Localized use of clodronate could be beneficial therapeutic adjunct for
orthodontic treatment and having an anti inflammatory properties may also be
helpful in the treatment of increased bone resorption associated with
inflammatory diseases such as rheumatoid arthritis and periodontitis.
• This class of agents selectively inhibits osteoclasts, it has been used to
treat various metabolic bone diseases associated with excessive bone
resorption
• Lab studies have demonstrated that orthodontic tooth movement can be
inhibited by the topical application of bisphosphonates.
• In 1994, Adachi and colleagues suggested that topically applied
bisphosphonates could be useful in orthodontic anchorage & retention of
teeth.
• In 2004, Liu and colleagues applied a bisphosphonate without a nitrogen
atom (clodronate) in the subperiosteal molar regions of rats submitted to
orthodontic forces for three weeks.
• Local applications of clodronate not only reduced the amount of
orthodontic movement and the no. of osteoclasts, but also reduced root
resorption.
• In 2005, Schwartz reported an important case of a female orthodontic
patient who was being medicated with Zometa to control bone
metastases related to breast cancer. At the time the patient began
treatment with this drug, when the premolar spaces were about one-
third closed, all orthodontic movement stopped.
• Therefore further studies required before these drugs can be used in
clinical orthodontic therapy
• Also demonstrated a dose-dependent reduction of root resorption,
when administered in rats . However, it has also been reported that
these drugs produce cemental surface alterations, by inhibiting acellular
cementum formation, thereby actually increasing the vulnerability of the
dental root to the resorptive process
• In the initial stage of lower drug concentrations, osteoclastic activity is
decreased with the balance shifting to more osteoblastic activity, causing
increased bone formation.
• In the midstage, drug concentrations rise, causing osteoclastic activity to
decrease further. This might start to decrease both osteoblastic activity
and new capillary formation in new bone, observed as decreased bone
turnover and bone repair.
• In the later stage, the drug might greatly accumulate in alveolar bones in
the maxilla and the mandible. Osteoclastic activity is decreased enough
not to allow normal removal of diseased bone. New bone is laid over
defective bone with decreased capillary formation and blood supply.
This can be observed as induced osteopetrosis.
• In the final stage of excessive drug accumulation, programmed cell death
occurs more rapidly, and vascular compromised bone might not be able
to regenerate from the micro-trauma of continuous mastication.
• This can ultimately be observed as osteonecrosis. The addition of

extractions, trauma, secondary infection, periodontal disease, and bone

augmentation might accelerate osteonecrosis by exceeding the osseous

repair capacity of hypodynamic bone.

• No studies have attributed orthodontic treatment to increased

osteonecrosis risks.

• Future studies are needed to correlate histology, bone mineral densities,

radiographic markers (such as technetium99), and biochemical markers

for bone deposition (bone-specific alkaline phosphatase or osteocalcin)

and bone resorption (N or C telopeptides) to provide information about

drug accumulation staging to determine procedural risks.

 LONG-TERM ORAL BISPHOSPHONATE TREATMENT
• It is expected that more osteonecrosis cases will be reported in the future
for the following reasons.
• 1. More patients are being treated with oral nitrogen containing
bisphosphonates that can preferentially accumulate in the alveolar bones
of the maxilla and the mandible.
• 2. Constant administration of oral bisphosphonates might allow them to
remain in the alveolar bone for long periods. There might be local cycles
of binding and releasing the drug in higher concentrations due to
increased alveolar bone turnover through normal mastication, trauma,
and infection.
• 3. The dental community is increasingly aware of Osteonecrosis linked
to oral bisphosphonate treatment.
 PROPOSED ORTHODONTIC RECOMMENDATIONS
• Zahrowski propose the following recommendations for patients receiving
bisphosphonate treatment. These recommendations are to be used for professional
guidance and are not to be interpreted as the standard of care
• Ask all patients whether they currently take or have ever taken IV or oral
bisphosphonates and ask the medical reason for treatment (severe bone disorders,
cancers, osteoporosis/osteopenia) on your screening/ medical history form.
• Determine
• the risk of osteonecrosis and the level of osteoclastic inhibition:
• route of administration and reason for bisphosphonate treatment IV
bisphosphonate treatment for severe bone disorders and cancers has high risk of
osteonecrosis and high level of osteoclastic inhibition. Oral bisphosphonate
treatment for osteoporosis or osteopenia has a lower risk of osteonecrosis and
lower level of osteoclastic inhibition);
• duration of treatment (longer duration is associated with more risk); dose and
frequency (presume that a higher dose or more frequent administration leads to
higher risks).
• Evaluate treatment plan based on risk group.

• If a patient has high risk/high level of osteoclastic inhibition (IV

bisphosphonates), avoid orthodontic treatment
possible strong inhibition of tooth movement,

intensifying local bisphosphonate uptake and release, and

increasing demand for osseous repair that might exceed compromised alveolar

bone capability

• Patients who have started IV bisphosphonate treatment need retainers checked

for passive retention and be relieved of any tissue pressure; they also need areas
monitored for open necrotic bone, especially in posterior, lingual mandibular
areas, mandibular tori, and midline palatal tori.

• Passive tooth-borne retainers can be considered.

• Elective surgeries should be avoided (extractions, implants, periodontal

surgeries) after IV bisphosphonates.
 • The objective is to keep the mucosa intact and avoid exposing any underlying
necrotic bone.

• Root canal treatment is considered more conservative than extraction.

• Teeth with grade 1 or 2 mobility can be splinted.

• Teeth with grade 3 mobility are strongly associated with periodontal abscesses
and osteonecrosis.

• Dental alveolar surgeries or extractions are recommended only when infection

cannot be managed by conservative measures and should be performed by a
specialist knowledgeable about bisphosphonate osteonecrosis.

• If there is low risk/lower level of osteoclastic inhibition (oral bisphosphonates)

• Counsel patients about inhibited tooth movement, osteonecrosis, and
impaired bone healing with elective surgery procedures

• Monitor for signs and symptoms of later drug accumulation effects and
possible osteonecrosis
 Sex steroid
• Sex steroids, also known as gonadal steroids, are steroid hormones that interact
with vertebrate androgen or estrogen receptors. The term sex hormone nearly always
is synonymous with sex steroid.
• Types
• In many contexts, the two main classes of sex steroids are androgens and estrogens,
of which the most important human derivatives are testosterone and estradiol,
respectively. Other contexts will include progestagen as a third class of sex steroids,
distinct from androgens and estrogens. Progesterone is the most important and only
naturally-occurring human progestagen.
• Sex steroids include:
• Androgens:
• testosterone
• androstenedione
• dihydrotestosterone
• dehydroepiandrosterone
• anabolic steroids
• Estrogens:
• estradiol
• estrone
• Progestagens:
• progesterone
• progestins
• The ovaries of sexually-mature females secrete:
• a mixture of estrogens of which 17β-estradiol is the most abundant
(and most potent).
• progesterone.
• Estrogens
• They are primarily responsible.
• development of breasts
• further development of the uterus and vagina
• broadening of the pelvis
• growth of pubic and axillary hair
• increase in adipose (fat) tissue
• participate in the monthly preparation of the body for a possible
pregnancy
• participate in pregnancy if it occurs
• Estrogens also have non-reproductive effects.
• They antagonize the effects of the parathyroid hormone, minimizing the
loss of calcium from bones and thus helping to keep bones strong.
• They promote blood clotting.
• The principal androgen (male sex hormone) is testosterone. This steroid
is manufactured by the interstitial (Leydig) cells of the testes. Secretion
of testosterone increases sharply at puberty and is responsible for the
development of the so-called secondary sexual characteristics (e.g.,
beard) of men.
• Testosterone is also essential for the production of sperm.
• Production of testosterone is controlled by the release of luteinizing
hormone (LH) from the anterior lobe of the pituitary gland, which is in
turn controlled by the release of GnRH from the hypothalamus. LH is
also called interstitial cell stimulating hormone (ICSH).
• Hypothalamus → GnRH→ Pituitary→LH→Testes→Testosterone
• The level of testosterone is under negative-feedback control: a rising
level of testosterone suppresses the release of GnRH from the
hypothalamus. This is exactly parallel to the control of estrogen secretion
in females.
• Estrogen is considered the most important hormone affecting bone
metabolism in women.
• It inhibits
• the production of cytokines involved in osteoclastic activation &
• bone resorption, such as IL-1, TNF-a & IL-6.
• In 2001, Yamashiro & Takano Yamamoto demonstrated an acceleration of
tooth movement in sprayed female rats.
• In 1996, Miyajima & colleagues attributed a female patients slow turnover
of alveolar bone to her menopausal status and to the estrogen
supplement she had been taking for three years
• They also suggested that young women taking oral contraceptives might
experience a reduced rate of tooth movement, although further studies
are required in this area.
• The inhibitory effect of androgens on bone resorption has been
demonstrated, but their influence on orthodontic tooth movement has
not been clarified.
 Relaxin

• Relaxin is a peptide hormone that was first described in 1926 by

Frederick Hisaw. Different forms of relaxin have been described:
relaxin 1, 2, and 3

• In the female, it is produced by

• the corpus luteum of the ovary,

• the breast and during pregnancy,

• also by the placenta, chorion, and decidua.

• In the male, relaxin is produced in the testes

• Function

• The function of relaxin in humans is not clear, although it has several

functions in animals.

• In humans
• In women relaxin levels rise after ovulation as a result of its production by
the corpus luteum.

• In the absence of pregnancy its level declines at menstruation.

• During the first trimester of pregnancy levels rise and additional relaxin is
produced by the decidua.

• Relaxin's role or necessity in human pregnancy remains under investigation,

as in humans its peak is reached during the first trimester, not toward the
end of pregnancy.
• In animals
• In animals relaxin widens the pubic bone and facilitates labor, it also
softens the cervix (cervical ripening), and relaxes the uterine
musculature.
• Thus, for a long time, relaxin was looked at as a pregnancy hormone.
However, its significance may reach much further.
• Relaxin affects collagen metabolism, inhibiting collagen synthesis
and enhancing its breakdown by increasing matrix
metalloproteinase.
• It also enhances angiogenesis and is a potent renal vasodilator.
Disorders
• Specific disorders related to relaxin have not been described, yet it
has been suggested that it could be linked to scleroderma and to
fibromyalgia.
• Relaxin ‘s influence on soft tissue remodeling and on several mediators that
stimulate osteoclast formation has attracted attention from orthodontic
researchers.
• In 2005, Liu and colleagues showed that the administration of human relaxin
might accelerate the early stages of orthodontic tooth movement in rats.
• Stewart and colleagues used gingival injection of relaxin in dogs to relieve
rotational memory in the connective tissues of maxillary second incisors that
had been orthodontically rotated. Results were not significant, but the authors
suggested that a refinement of the dosages and treatment techniques might
improve in future studies.
• In 2000, Nicozisis and colleagues demonstrated that the presence of relaxin
abolished the integrity of sutures in-vitro.
• These authors suggested that relaxin might be used as an adjunct to orthodontic
therapy,
• during or after tooth movement,
• for promotion of stability,
• for rapid remodeling of gingival tissue during extraction space closure or
• for orthopedic expansion in non-growing patients, by reducing the tension of
stretched soft tissue envelope, particularly the expanded palatal mucosa, after
orthognathic surgery.
• Although these clinical finding will hold true in clinical practice remains to be
investigated.
 Thyroid hormone

• The thyroid hormones, thyroxine (T4) and triiodothyronine (T3), are

tyrosine-based hormones produced by the thyroid gland.

• An important component in the synthesis is iodine.

• The major form of thyroid hormone in the blood is thyroxine (T4).

• The ratio of T4 to T3 released in the blood is roughly 20 to 1.

Thyroxine is converted to the active T3 (three to four times more

potent than T4) within cells by deiodinases (5'-iodinase). These are

further processed by decarboxylation and deiodination to produce

iodothyronamine (T1a) and thyronamine (T0a).

• Circulation
• Most of the thyroid hormone circulating in the blood is bound to
transport proteins. Only a very small fraction of the circulating hormone
is free (unbound) and biologically active, hence measuring
concentrations of free thyroid hormones is of great diagnostic value.
• When thyroid hormone is bound, it is not active, so the amount of free
T3/T4 is what is important. For this reason, measuring total thyroxine in
the blood can be misleading.
• Type
• bound to thyroxine-binding globulin (TBG)70%
• bound to transthyretin or "thyroxine-binding prealbumin" (TTR or TBPA)10-
15%
• albumin15-20%
• unbound T4 (fT4)0.03%
• unbound T3 (fT3)0.3%
• T3 and T4 cross the cell membrane, probably via amino acid importins,

and function via a well-studied set of nuclear receptors in the nucleus of

the cell, the thyroid hormone receptors.

• T1a and T0a are positively charged and do not cross the membrane; they

are believed to function via the trace amine-associated receptor TAAR1

(TAR1, TA1), a G-protein-coupled receptor located in the cell membrane.

• Another critical diagnostic tool is the amount of thyroid-stimulating

hormone (TSH) that is present.

• Function
• The thyronines act on the body
• to increase the basal metabolic rate,
• affect protein synthesis and
• increase the body's sensitivity to catecholamines (such as adrenaline)
by permissiveness.
• The thyroid hormones are essential for proper development and
differentiation of all cells of the human body.
• regulate protein, fat, and carbohydrate metabolism,
• They also stimulate vitamins metabolism.
• Numerous physiological and pathological stimuli influence thyroid
hormone synthesis.
• The thyronamines function via some unknown mechanism to inhibit
neuronal activity; this plays an important role in the hibernation
cycles of mammals and the moulting behaviour of birds. One effect
of administering the thyronamines is a severe drop in body
temperature.
• Related diseases

• Both excess and deficiency of thyroxine can cause disorders.

• Thyrotoxicosis or hyperthyroidism (more specifically Graves Disease) is

the clinical syndrome caused by an excess of circulating free thyroxine,
free triiodothyronine, or both. It is a common disorder that affects
approximately 2% of women and 0.2% of men.

• Hypothyroidism (an example is Hashimoto's thyroiditis) is the case

where there is a deficiency of thyroxine, triiodiothyronine, or both.

• Clinical depression can sometimes be caused by hypothyroidism.

• Some research has shown that T3 is found in the junctions of synapses,

and regulates the amounts and activity of serotonin, norepinephrine,
and Gamma-aminobutyric acid (GABA) in the brain.
• Effects of thyroxine
• Increases cardiac output
• Increases heart rate
• Increases ventilation rate
• Increases basal metabolic rate
• Potentiates brain development
• Thickens endometrium in females
• Thyroid hormones play an essential role in the normal growth and
development of vertebrates.
• They enhance the response to growth hormone, stimulate cartilage
growth and differentiation and promote bone maturation and resorption
.
• In bone remodeling, they act directly by stimulating the action of
osteoclasts, but they also have an indirect effect through growth factors
that are closely related to bone metabolism, such as insulin like growth
factor, which is produced locally in bone cells by the action of thyroid
hormones.
• In 1999, Shirazi and colleagues, thyroid hormone administration not only
increased the rate of tooth movement in rats, but also reduced the extent
of root resportion, as seen from scanning electron micrographs.
• In 1994, Poumpros and colleagues reported a protective effect from
thyroxin on root resorptive lesions that had been induced by the
application of orthodontic forces.
• More recently, Vazquez Landaverde and colleagues showed that animals
treated with thyroid hormones (intraperitoneal or oral) had significantly
less force induced root resorptive lesions than were found in a control
group
• They also suggested that low doses of thyroid hormones may have a
protective effect on root surfaces, either during orthodontic treatment or
in patients who present spontaneous root resorptive lesions
• The clinical application of these drugs still need to be clarified.
• The main hormone prescribed to reduce root resorption is L-thyroxine,
which increases the resistance of cementum and dentin to clastic activity.
• Shirazi et al. have confirmed this finding through the administration of
increased doses of L-thyroxine to rats, which resulted in the reduction of
the extent of root resorption .
• However, the resultsof the rat studies should be viewed with caution as
no human trials on the use of L-thyroxine have been reported till now.
 Parathyroid hormone

• Parathyroid hormone (PTH), or parathormone, is secreted by the

parathyroid glands as a polypeptide containing 84 amino acids.

• It acts to increase the concentration of calcium (Ca2+) in the blood,

whereas calcitonin (a hormone produced by the parafollicular cells (C

cells) of the thyroid gland) acts to decrease calcium concentration.

• PTH acts to increase the concentration of calcium in the blood by acting

upon parathyroid hormone receptor in three parts of the body

 Functions
Effects on serum calcium (raising)

Region Effect

Bones
it enhances the release of calcium from the large reservoir contained in the bones.

Bone resorption is the normal destruction of bone by osteoclasts, which are indirectly stimulated by PTH.

Stimulation is indirect since osteoclasts do not have a receptor for PTH; rather, PTH binds to osteoblasts, the cells

responsible for creating bone.

Binding stimulates osteoblasts to increase their expression of RANKL, which can bind to osteoclast precursors

containing RANK, a receptor for RANKL. The binding of RANKL to RANK stimulates these precursors to fuse,

forming new osteoclasts which ultimately enhances the resorption of bone.

Kidney It enhances active reabsorption of calcium from distal tubules and the thick ascending limb.

Intestine
It enhances the absorption of calcium in the intestine by increasing the production of activated vitamin D. Vitamin D
via
kidney activation occurs in the kidney.

PTH up-regulates the enzyme responsible for 1-alpha hydroxylation of 25-hydroxy vitamin D, converting vitamin D to
its active form (1,25-dihydroxy vitamin D).

This actived form of vitamin D affects the absorption of calcium (as Ca2+ ions) by the intestine via calbindin. It enhances
the absorption of calcium in the intestine by increasing the production of activated vitamin D. Vitamin D activation
occurs in the kidney.

PTH up-regulates the enzyme responsible for 1-alpha hydroxylation of 25-hydroxy vitamin D, converting vitamin D to
its active form (1,25-dihydroxy vitamin D). This actived form of vitamin D affects the absorption of calcium (as Ca2+
ions) by the intestine via calbindin.
• Effects on serum phosphate (decrease, with compensation)

• PTH reduces the uptake of phosphate from the proximal tubule of the

kidney which means more phosphate is excreted through the urine.

• However, PTH also enhances the uptake of phosphate from the intestine

and bones into the blood.

• Slightly more calcium than phosphate is released from the breakdown of

bone, and the intestinal absorption of phosphate (mediated by an

increase in activated vitamin D) is not as dependent on vitamin D as is

that of calcium. The end result is a small net drop in the serum

concentration of phosphate.
• Feedback regulation
• Increased calcium concentration in the blood acts (via feedback
inhibition) to decrease PTH secretion by the parathyroid glands.
• This is achieved by the activation of calcium-sensing receptors located
on parathyroid cells.
• Syndromes
• A high level of PTH in the blood is known as hyperparathyroidism.
• If the cause is in the parathyroid gland it is called primary
hyperparathyroidism. The causes are parathyroid adenoma,
parathyroid hyperplasia and parathyroid cancer. secondary
• If the cause is outside the gland, it is known as hyperparathyroidism.
This can occur in chronic renal failure.
• A low level of PTH in the blood is known as hypoparathyroidism.
Causes include surgical misadventure (eg inadvertent removal during
routine thyroid surgery), autoimmune disorder, and inborn errors of
metabolism.
• In 1970s , animal studies demonstrated that PTH could induce an increase

in bone turnover that would accelerate orthodontic movement.

• More recently, Soma and colleague observed an increase rate of tooth

movement in rats treated with PTH, whether administered locally or

systemically.

• These results indicate that orthodontists should take note of patients

being treated with PTH (osteoporosis).

 Vitamin D
• Vitamin D is a group of fat-soluble prohormones
• Several forms of vitamin D have been discovered.
• Vitamin D1: molecular compound of ergocalciferol with lumisterol,
1:1
• Vitamin D2: ergocalciferol or calciferol (made from ergosterol)
• Vitamin D3: cholecalciferol (made from 7-dehydrocholesterol in the
skin).
• Vitamin D4: 22-dihydroergocalciferol
• Vitamin D5: sitocalciferol (made from 7-dehydrositosterol)
• The two major forms are vitamin D2 or ergocalciferol, and vitamin D3 or
cholecalciferol.
• Vitamin D3 is produced in skin exposed to sunlight, specifically
ultraviolet B radiation.
• Vitamin D plays an important role in the maintenance of organ systems.

• Vitamin D regulates the calcium and phosphorus levels in the blood by

promoting their absorption from food in the intestines, and by
promoting re-absorption of calcium in the kidneys.

• It promotes bone formation and mineralization and is essential in the

development of an intact and strong skeleton. Although, at very high
levels it will promote the resorption of bone.

• It inhibits parathyroid hormone secretion from the parathyroid gland.

• Vitamin D affects the immune system by promoting

immunosuppression, phagocytosis, and anti-tumor activity.
• Vitamin D deficiency can result
• From inadequate intake coupled with inadequate sunlight exposure,
• Disorders that limit its absorption, conditions that impair conversion
of vitamin D into active metabolites, such as liver or kidney
disorders,
• Rarely, by a number of hereditary disorders.
• Deficiency results in impaired bone mineralization, and leads to bone
softening diseases,
• Rickets in children and
• Osteomalacia in adults, and possibly contributes to osteoporosis.
• Research has indicated that vitamin D deficiency is linked to colon
cancer; conflicting evidence links vitamin D deficiency to other forms of
cancer
• Chemically, the various forms of vitamin D are secosteroids; i.e. broken-
open steroids.
• The structural difference between vitamin D2 and vitamin D3 is in their
side chains.
• The side chain of D2 contains a double bond between carbons 22 and 23,
and a methyl group on carbon 24.
• Vitamin D2 is derived from fungal and plant sources, and is not
produced by the human body.
• Vitamin D3 is derived from animal sources and is made in the skin when
7-dehydrocholesterol reacts with UVB ultraviolet light at wavelengths
between 270–290 nm.
• In most mammals, including humans, D3 is more effective than D2 at
increasing the levels of vitamin D hormone in circulation; D3 is at least
3-fold, and likely closer to 10-fold, more potent than D2.
• However, in some species, such as rats, vitamin D2 is more effective than
D3.
• Both vitamin D2 and D3 are used for human nutritional
supplementation, and pharmaceutical forms include calcitriol (1alpha,
25-dihydroxycholecalciferol), doxercalciferol and calcipotriene.
• Production in the skin
• The skin consists of two primary layers: the inner layer called the
dermis, composed largely of connective tissue and the outer thinner
epidermis.
• The epidermis consists of five strata; from outer to inner they are:
• stratum corneum,
• stratum lucidum,
• stratum granulosum,
• stratum spinosum,
• stratum basale.

• Vitamin D3 is produced photochemically in the skin from 7-

dehydrocholesterol. The highest concentrations of 7-dehydrocholesterol
are found in the epidermal layer of skin, specifically in the stratum
basale and stratum spinosum.
• The production of pre-vitamin D3 is therefore greatest in these two
layers, whereas production in the other layers is reduced.
• Synthesis in the skin involves UVB radiation which effectively penetrates
only the epidermal layers of skin.
• 7-Dehydrocholesterol absorbs UV light most effectively at wavelengths
between 270–290 nm and thus the production of vitamin D3 will only occur
at this wavelengths.
• The two most important factors that govern the generation of pre-vitamin
D3 are the quantity (intensity) and quality (appropriate wavelength) of the
UVB irradiation reaching the 7-dehydrocholesterol deep in the stratum
basale and stratum spinosum.
• A critical determinant of vitamin D3 production in the skin is the presence
and concentration of melanin. Melanin functions as a light filter in the skin,
and therefore the concentration of melanin in the skin is related to the ability
of UVB light to penetrate the epidermal strata and reach the 7-
dehydrocholesterol-containing stratum basale and stratum spinosum. Under
normal circumstances, ample quantities of 7-dehydrocholesterol (about 25-
50 mg/cm² of skin) are available in the stratum spinosum and stratum
basale of human skin to meet the body's vitamin D requirements, and
melanin content does not alter the amount of vitamin D that can be
produced. Thus, individuals with higher skin melanin content will simply
require more time in sunlight to produce the same amount of vitamin D as
individuals with lower melanin content.
Synthesis mechanism (form 3)
1. Vitamin D3 is synthesized from 7-dehydrocholesterol, a derivative of
cholesterol, which is then photolyzed by ultraviolet light in 6-electron
conrotatory electrocyclic reaction. The product is pre-vitamin D3.

• 2. Pre-vitamin D3 then spontaneously isomerizes to Vitamin D3 in a

antarafacial hydride [1,7]Sigmatropic shift.
• 3. Whether it is made in the skin or ingested, vitamin D3 (cholecalciferol) is
then hydroxylated in the liver to 25-hydroxycholecalciferol (25(OH)D3 or
calcidiol) by the enzyme 25-hydroxylase produced by hepatocytes, and
stored until it is needed
• 25-hydroxycholecalciferol is further hydroxylated in the kidneys by the
enzyme 1α-hydroxylase, into two dihydroxylated metabolites, the main
biologically active hormone 1,25-dihydroxycholecalciferol (1,25(OH)2D3 or
calcitriol) and 24R,25(OH)2D3. This conversion occurs in a tightly regulated
fashion.

Calcitriol is represented below right (hydroxylated Carbon 1 is on the lower

ring at right, hydroxylated Carbon 25 is at the upper right end).
• Mechanism of action
• Once vitamin D is produced in the skin or consumed in food, it is converted
in the liver and kidney to form 1,25 dihydroxyvitamin D, (1,25(OH)2D) the
physiologically active form of vitamin D (when "D" is used without a
subscript it refers to either D2 or D3). Following this conversion, the
hormonally active form of vitamin D is released into the circulation, and by
binding to a carrier protein in the plasma, vitamin D binding protein
(VDBP), it is transported to various target organs.
• The hormonally active form of vitamin D mediates its biological effects by
binding to the vitamin D receptor (VDR), which is principally located in the
nuclei of target cells. The binding of calcitriol to the VDR allows the VDR to
act as a transcription factor that modulates the gene expression of transport
proteins (such as TRPV6 and calbindin), which are involved in calcium
absorption in the intestine.
• The Vitamin D receptor belongs to the nuclear receptor superfamily of
steroid/thyroid hormone receptors, and VDR are expressed by cells in most
organs, including the brain, heart, skin, gonads, prostate, and breast. VDR
activation in the intestine, bone, kidney, and parathyroid gland cells leads to
the maintenance of calcium and phosphorus levels in the blood (with the
assistance of parathyroid hormone and calcitonin) and to the maintenance of
bone content.
• The VDR is known to be involved in cell proliferation, differentiation.
Vitamin D also affects the immune system, and VDR are expressed in
several white blood cells including monocytes and activated T and B cells.
• Nutrition
• Very few foods are naturally rich in vitamin D, and most vitamin D intake is in
the form of fortified products including milk, soy milk and cereal grains.[1]
• A blood calcidiol (25-hydroxy-vitamin D) level is the accepted way to determine
vitamin D nutritional status. The optimal level of serum 25-hydroxyvitamin D
remains a point for debate among medical scientists.
• Adequate Intake (AI) of vitamin D for infants, children and men and women aged 19–
50 is 5 micrograms/day (200 IU/day).
• Adequate intake increases to 10 micrograms/day (400 IU/day) for men and women
aged 51–70
• And to 15 micrograms/day (600 IU/day) past the age of 70.

• These dose rates will be too low during winter months .

• In the absence of sun exposure,
• 1000 IU of cholecalciferol is required daily for children.
• 2000-4000 IU of vitamin D may be required for adults
• Milk and cereal grains are often fortified with vitamin D.
• Season, geographic latitude, time of day, cloud cover, smog, and
sunscreen affect UV ray exposure and vitamin D synthesis in the skin,
and it is important for individuals with limited sun exposure to include
good sources of vitamin D in their diet.
• In some countries, foods such as milk, yogurt, margarine, oil spreads,
breakfast cereal, pastries, and bread are fortified with vitamin D2 and/or
vitamin D3, to minimize the risk of vitamin D deficiency
• Fatty fish, such as salmon, are natural sources of vitamin D.
• Fortified foods represent the major dietary sources of vitamin D, as very
few foods naturally contain significant amounts of vitamin D.

Milk and cereal grains Fatty fish, such as salmon, are

are often fortified with natural sources of vitamin D
vitamin D.
• Natural sources of vitamin D include:
• Fish liver oils, such as cod liver oil, 1 Tbs. (15 mL) provides 1,360 IU
• Fatty fish species, such as:
• Catfish, 3 oz provides 425 IU
• Salmon, cooked, 3.5 oz provides 360 IU
• Mackerel, cooked, 3.5 oz, 345 IU
• Sardines, canned in oil, drained, 1.75 oz, 250 IU
• Tuna, canned in oil, 3 oz, 200 IU
• Eel, cooked, 3.5 oz, 200 IU
• Mushrooms provide over 2700 IU per serving (approx. 3 oz or 1/2
cup) of vitamin D2, if exposed to just 5 minutes of UV light after being
harvested;[13] this is one of a few natural sources of vitamin D for
vegans.
• One whole egg, 20 IU
• Diseases caused by deficiency
• The role of diet in the development of rickets was determined by Edward
Mellanby between 1918–1920.
• In 1921 Elmer McCollum identified an anti-rachitic substance found in
certain fats could prevent rickets. Because the newly discovered substance
was the fourth vitamin identified, it was called vitamin D.
• The 1928 Nobel Prize in Chemistry was awarded to Adolf Windaus, who
discovered the steroid 7-dehydrocholesterol, the precursor of vitamin D.
• Vitamin D deficiency is known to cause several bone diseases including:
• Rickets, a childhood disease characterized by impeded growth, and deformity, of
the long bones.
• Osteomalacia, a bone-thinning disorder that occurs exclusively in adults and is
characterized by proximal muscle weakness and bone fragility.
• Osteoporosis, a condition characterized by reduced bone mineral density and
increased bone fragility.
• Prior to the fortification of milk products with vitamin D, rickets was a major
public health problem.
• Vitamin D malnutrition may also be linked to an increased susceptibility to
several chronic diseases such as high blood pressure, tuberculosis, cancer,
periodontal disease, multiple sclerosis, chronic pain, depression, schizophrenia,
seasonal affective disorder, and several autoimmune diseases including type 1
diabetes
• Groups at greater risk of deficiency
• Vitamin D requirements increase with age, while the ability of skin to
convert 7-dehydrocholesterol to pre-vitamin D3 decreases. In addition
the ability of the kidneys to convert calcidiol to its active form also
decreases with age, prompting the need for increased vitamin D
supplementation in elderly individuals. One consensus concluded that
for optimal prevention of osteoporotic fracture the blood calcidiol
concentration should be higher than 30 ng/mL, which is equal to 75
nmol /L.
• Obese individuals may have lower levels of the circulating form of
vitamin D, probably because of reduced bioavailability, and are at higher
risk of deficiency. To maintain blood levels of calcium, therapeutic
vitamin D doses are sometimes administered (up to 100,000 IU or 2.5 mg
daily) to patients who have had their parathyroid glands removed (most
commonly renal dialysis patients who have had tertiary
hyperparathyroidism, but also to patients with primary
hyperparathyroidism) or with hypoparathyroidism. Patients with
chronic liver disease or intestinal malabsorption disorders may also
require larger doses of vitamin D (up to 40,000 IU or 1 mg
(1000 micrograms) daily).21
• The use of sunscreen with a sun protection factor (SPF) of 8 inhibits more
than 95% of vitamin D production in the skin. Recent studies showed
that, following the successful "Slip-Slop-Slap" health campaign
encouraging Australians to cover up when exposed to sunlight to
prevent skin cancer, an increased number of Australians and New
Zealanders became vitamin D deficient. Ironically, there are indications
that vitamin D deficiency may lead to skin cancer. To avoid vitamin D
deficiency dermatologists recommend supplementation along with
sunscreen use.
• The reduced pigmentation of light-skinned individuals tends to allow more sunlight
to be absorbed even at higher latitudes, thereby reducing the risk of vitamin D
deficiency. However, at higher latitudes (above 30°) during the winter months, the
decreased angle of the sun's rays, reduced daylight hours, protective clothing during
cold weather, and fewer hours of outside activity, diminish absorption of sunlight
and the production of vitamin D. Because melanin acts like a sun-block, prolonging
the time required to generate vitamin D, dark-skinned individuals, in particular,
may require extra vitamin D to avoid deficiency at higher latitudes. In June 2007, The
Canadian Cancer Society began recommending that all adult Canadians consider
taking 1000 IU of vitamin D during the fall and winter months (when typically the
country's northern latitude prevents sufficient sun-stimulated production of vitamin
D). At latitudes below 30° where sunlight and day-length are more consistent,
vitamin D supplementation may not be required. Individuals clad in full body
coverings during all their outdoor activity, most notably women wearing burquas in
daylight, are at risk of vitamin D deficiency. This poses a lifestyle-related health risk
mostly for female residents of conservative Muslim nations in the Middle East, but
also for strict adherents in other parts of the world.
• Overdose
• Vitamin D stored in the human body as calcidiol (25-hydroxy-vitamin D) has a large
volume of distribution and a long half-life (about 20 to 29 days). However, the
synthesis of bioactive vitamin D hormone is tightly regulated and vitamin D toxicity
usually occurs only if excessive doses are taken. Although normal food and pill
vitamin D concentration levels are too low to be toxic in adults, because of the high
vitamin A content in codliver oil, it is possible to reach toxic levels of vitamin A (but
not vitamin D) via this route, if taken in multiples of the normal dose in an attempt
to increase the intake of vitamin D. Most historical cases of vitamin D overdose have
occurred due to manufacturing and industrial accidents.[28]
• Exposure to sunlight for extended periods of time does not cause vitamin D
toxicity.[28] This is because within about 20 minutes of ultraviolet exposure in light
skinned individuals (3–6 times longer for pigmented skin) the concentration of
vitamin D precursors produced in the skin reach an equilibrium, and any further
vitamin D that is produced is degraded.[29] Maximum endogenous production with
full body exposure to sunlight is 250 µg (10,000 IU) per day.[28]
• The exact long-term safe dose of vitamin D is not entirely known, but dosages up to
60 micrograms (2,400 IU) /day in healthy adults are believed to be safe. and all
known cases of vitamin D toxicity with hypercalcemia have involved intake of or
over 1,000 micrograms (40,000 IU)/day.
• The U.S. Dietary Reference Intake Tolerable Upper Intake Level (UL) of vitamin D for
children and adults is 50 micrograms/day (2,000 IU/day). In adults, sustained intake of
2500 micrograms/day (100,000 IU) can produce toxicity within a few months. For infants
(birth to 12 months) the tolerable UL is set at 25 micrograms/day (1000 IU/day), and
vitamin D concentrations of 1000 micrograms/day (40,000 IU) in infants has been shown
to produce toxicity within 1 to 4 months
• In healthy individuals, calcidiol levels are normally between 25 to 40 ng/mL (60 to 100
nmol/L), but these levels may be as much as 15-fold greater in cases of vitamin D toxicity.
• Serum levels of bioactive vitamin D hormone (1,25(OH2)D) are usually normal in cases of
vitamin D overdose.
• Some symptoms of vitamin D toxicity are a result of hypercalcemia (an elevated level of
calcium in the blood) caused by increased intestinal calcium absorption.
• Vitamin D toxicity is known to be a cause of high blood pressure. Gastrointestinal
symptoms of vitamin D toxicity can include anorexia, nausea, and vomiting. polyuria,
polydipsia ,weakness, nervousness, pruritus (itch), and eventually renal failure. Other
signals of kidney disease including elevated protein levels in the urine, urinary casts, and
a build up of wastes in the blood stream can also develop .In one study, hypercalciuria
and bone loss occurred in four patients with documented vitamin D toxicity. Another
study showed elevated risk of ischaemic heart disease when 25D was above 89 ng/mL.
• Vitamin D toxicity is treated by discontinuing vitamin D supplementation, and restricting
calcium intake. If the toxicity is severe blood calcium levels can be further reduced with
corticosteroids or bisphosphonates. In some cases kidney damage may be irreversible
• Role in cancer prevention and recovery
• The vitamin D hormone, calcitriol, has been found to induce death of
cancer cells in vitro and in vivo. Although the anti-cancer activity of
vitamin D is not fully understood, it is thought that these effects are
mediated through vitamin D receptors expressed in cancer cells, and
may be related to its immunomodulatory abilities. The anti-cancer
activity of vitamin D observed in the laboratory has prompted some to
propose that vitamin D supplementation might be beneficial in the
treatment or prevention of some types of cancer
• Role in coronary disease prevention
• Research indicates that vitamin D plays a role in preventing or reversing
coronary disease. As with cancer incidence, the same qualitative inverse
correlations exist between coronary disease incidence and serum vitamin
D levels, seasonal solar exposure, in temperate latitudes but not tropical
latitudes
• In 1988, Collins and Sinclair demonstrated that intraligamentous
injections of a vitamin D metabolite, 1,25-dihydroxycholecalciferol(
1,25D), caused an increase in the no. of osteoclasts and the amount of
tooth movement during canine retraction with light forces in cats.
• Similar results were observed by Takano-Yamamoto and colleagues in 1992
• Corroborating these findings, Kale and colleagues in 2004 observed that
local application of vitamin D enhanced the rate of tooth movement in
rats
• According them this effect was due to well balanced bone turnover
induced by vitamin D.
• In addition , the stimulatory action of vitamin D on osteoblast can help
stabilize orthodontic movement.
• In 1996, Baran and colleagues, treated rats with vitamin D showed
increased bone formation on the pressure side of the periodontal
ligament after the application of orthodontic forces.
• In 2004, Kawakami and Takano-Yamamoto also observed an increased in
the mineral appositional rate on alveolar bone after the application of
orthodontic forces in rats.
• They suggested that local application of vitamin D could intensify the
reestablishment of supporting tissue, especially alveolar bone, after
orthodontic treatment.
 Conclusion
• Orthodontists have long observed that teeth move at different rates , and
that individuals have differing responses to treatment .
• Some of these differences are caused by changes in bone remodeling
induced by drugs and systemic factors.
• NSAIDs (except celecoxib), bisphosphonates and sex hormones can
reduce the rate of orthodontic movement, while corticosteroids, relaxin,
thyroid hormones, PTH, and vitamin D can increase the rate of tooth
movement.
• Therefore clinicians should pay careful attention to the medications
being used by their patients, so that the best treatment strategy,
including force control and appointment intervals can be selected for
each case
• Acetaminophen which does not have a significant influence on the rate
of tooth movement, can be recommended for controlling pain during
orthodontic treatment.
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• This is a report of an exploratory study of how the hormone relaxin might modulate the
remodeling of connective tissue within the craniofacial sutures and periodontal tissues. Relaxin
is a hormone that was discovered to be produced by the pregnant female. It is responsible for
the relaxing of the pubic symphysis; the birth canal is widened for parturition. It has also been
shown to have effects on other areas of the body, including ligaments and regions containing
collagen and fibroblastic activity. Twenty-one Swiss retired-breeder mice were used to:
• 1) immunohistochemically demonstrate the presence of relaxin within the sutures;
• 2) demonstrate its effects on the integrity of the suture-like tissues; and
• 3) assay its effects on protease activity.
• Relaxin in concentrations of 250 and 500 ng:ml was used in the treated samples and allowed to
incubate in complete tissue culture for 24 h. The results indicate the presence of relaxin within
the cranial suture. Histological observations revealed definite changes in the collagen fibril
arrangement in the PDL – from being dense and highly organized with a perpendicular
direction between tooth and bone to randomly organized and loose, lacking any direction
between tooth and bone. An elevation in the protease activity was evident in the relaxin-treated
samples. This naturally occurring hormone might be used as an adjunct to orthodontic therapy
as it appears to have the capacity to alter the physical properties of the connective tissue within
sutures, gingival tissue, and the PDL. Potential indications for use include instances of sutural
and soft tissue adaptation of orthopedic expansion in non-growing patients by a reduction in
the tension of the stretched soft tissue envelope following orthognathic surgery (particularly
the expanded palatal mucosa), periodontal ligament remodeling during or after tooth
movement promoting stability, rapid gingival tissue remodeling during space closure in
extraction sites, and by a decrease in the amount of scar tissue formation following
frenectomies.