bisphosphonates and orthodontics clinical implications.

Contents
Introduction
Promoter and Suppressor drugs
Bisphosphonates
History
Pharmacology and Pharmacokinetics of Bisphosphonates
Uses
Types of bisphosphonates
Mechanism of action
Antiangiogenic property
Bisphosphonate induced osteonecrosis
Osteonecrosis diagnosis
Orthodontic implications
Proposed orthodontic recommendations
Conclusion
Refrences
www.indiandentalacademy.com

Introduction
The awareness towards orthodontic treatment among general public has
risen a lot.
While adult patients have been welcome in orthodontic practices, they
present a number of challenges, not all of which are related to
malocclusions.
Orthodontic tooth movement is basically a biologic response towards a
mechanical force. Osteoclast and osteoblast cells mediate bone resorption
and apposition, which eventually produces tooth movement.
 Yamasaki , Davidovitch showed that the rate of orthodontic tooth
movement can be altered by applying certain drugs locally or systemically.

Promoter drugs
These agents basically enhance bone resorption. They couple with the
secondary and primary inflammatory mediators and enhance tooth
movement they are :-
i. Prostaglandins
ii. Leucotriens
iii. Cytokines
iv. Vitamin D
v. Osteocalcin
vi. Corticosteroids
Except vitamin d and Corticosteroids the other above said agents are not
that much widely used in medical profession. Since bone turn over rate
will be more for those patients under any of the above said drugs, care
should be taken by utilizing low forces or by giving increased duration
between appliance activation appointments.

Supressor drugs
These agents basically reduce bone resorption.
i. Nonsteroidal anti-inflammatory agents - they interfere with
archidonic acid metabolism, blocks production of primary and or
secondary messengers.
ii. Bisphosphonates – bind with calcium ions, promotes apoptosis of
working osteoclasts.
Since NSAIDs are freely available over the counter, patients should be advised
not to take these drugs during orthodontic treatment, without the dentist’s
knowledge. One drug of choice for the patients under orthodontic treatment
is acetaminophen , whose mode of action is central rather than peripheral .
Though not available over the counter awareness among orthodontists of
the effects of bisphosphonates, a commonly prescribed type of drug that can
inhibit tooth movement and increase serious osteonecrosis risks in the
alveolar bones of the maxilla and the mandible is to be raised.

Bisphosphonates
Bisphosphonates are drugs used to treat bone metabolism disorders
such as osteoporosis, bone diseases, and bone pain from some types of
cancer.
Bisphosphonates work by inhibiting bone resorption by osteoclasts, they
can have side effects in dental treatment, including inhibited tooth
movement, impaired bone healing, and induced osteonecrosis in the
maxilla and the mandible.
As orthodontists, we need to know the pharmacology of drugs that can
change bone physiology because they can hinder treatment and increase
morbidity.
These effects could mean additional patient counseling is needed, along
with informed consent, enhanced monitoring techniques, reporting of side
effects, and, perhaps, changes in treatment planning.www.indiandentalacademy.com

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

Pharmacology of
Bisphosphonates
 Bisphosphonates are stable analogues of pyrophosphate .
 Pyrophosphate has a P-O-P structure ,where two phosphate groups are linked by an
oxygen atom.
 Bisphosphonates, however, have a P-C-P structure, (central) carbon atom replacing the
oxygen.
 Side chains R1 and R2 are attached to the carbon atom and influence the
bisphosphonates ability to bind to bone, and their anti-resorptive ability.
 The long (R2) side chain determines the potency of the drug, while the short (R1) side
chain influences the pharmacokinetics.
 Bisphosphonates containing a primary nitrogen atom in the R2 side-chain (for example
pamidronate) are more potent than non-nitrogen bisphosphonates, (such as clodronate).
structure, such as zoledronic acid.

Pharmacokinetics Of
Bisphosphonates
The bioavailability of oral bisphosphonates is very low, usually less than
2%; that of a standard IV dose is 100%.
After bisphosphonate is in the bloodstream, it quickly binds to the exposed
hydroxyapatite in the osseous matrix, and the excess drug leaves the body
through the kidneys.
Generally, 50% to 60% of the drug is bound to bone, with the remainder
excreted through the kidneys rapidly over several hours.
However, more drug can be selectively bound to bone if more sites of
active bone turnover exist during this distribution time.

Trabecular bone, accounting for only 20% of the skeleton, has 80% of
bone turnover. Alendronate was shown to concentrate 2 to 3 times higher
in trabecular bone.
After the drug is bound to bone, it is considered inactive until it is released
during bone remodeling. The released drug might be transported into the
osteoclast, rebound to another site of exposed hydroxyapatite, or be
eliminated by the kidneys. When transported into the osteoclast cell, it
inhibits cell function and shortens cell life span.
 The amount of drug released from bone depends on the rate of bone
turnover.

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 and oxidronate 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 of
Bisphosphonates
Fever and flu like symptoms - this is more common when you have
the bisphosphonate as a drip (infusion).
Bisphosphonates can cause low levels of calcium in your blood
(hypocalcaemia), and reduce the levels of other minerals in your
blood.
Bone and joint pain
Change in your bowel movements - bisphosphonates can sometimes
cause constipation or diarrhoea.
Feeling sick - bisphosphonates can cause mild nausea.
Bisphosphonates can cause damage to your kidneys.
Osteonecrosis of the jaw.

Types of bisphosphonates
Non-nitrogenous
Non-N-containing bisphosphonates:
•Etidronate (Didronel)
•Clodronate (Bonefos, Loron)
•Tiludronate(Skelid)
Nitrogenous
N-containing bisphosphonates
Pamidronate(APD, Aredia)
Alendronate (Fosamax)
Ibandronate (Boniva)
Risedronate (Actonel)
Zoledronate (Zometa)

Bones are made of living tissue, and are
constantly changing. In healthy bones,
specialised bone cells constantly break
down and replace bone tissue. These
specialised bone cells are
Osteoclasts – which break down old
bone
Osteoblasts – which build new bone
This process is called bone remodelling
and is very well controlled. There is a fine
balance between the rates of bone
breakdown and growth, which keeps
bones strong and healthy.

Mechanism of action
Simple bisphosphonates are incorporated into osteoclasts and undergo
condensation with adenosine monophosphate(AMP) ,the metabolite
formed accumulates intracellularly disrupting cellular function and
resulting in apoptosis.
The nitrogen containing bisphosphonates , inhibit sterol synthesis via
inhibiting farnesyl diphosphate synthase (FPP) in the mevalonate
pathway,inducing osteoclast apoptosis and there by inhibiting bone
resorption.

Impaired Bone Healing
In the treatment of osteoporosis, oral bisphosphonates are used to decrease
bone loss, increase bone density, and thereby decrease the risk of bone
fractures.
Ironically, diminished or absence of healing for nonspinal bone fractures
was reported during routine activities for 9 patients taking oral
alendronate for 1 to 8 years.Five patients resumed normal bone healing
after discontinuing alendronate for 3 to 8 months. Four patients continued
to have decreased healing for up to 12 months.

The difference was attributed to variable bone turnover at different
skeletal sites.
Also, prolonged high doses of IV bisphosphonates in children have been
reported to cause brittle bones that are more susceptible to fractures.
 In patients receiving long-term bisphosphonates, clinicians should be
aware of impaired bone healing because of the reported decreased bone
and capillary formation.

Antiangiogenic property of
Bisphosphonates
Bisphosphonates have antiangiogenic properties that inhibit endothelial
proliferation and decrease capillary formation.
In alveolar bone, overaccumulation of bisphosphonates might cause lack
of capillary formation and decreased blood flow, and contribute to the
avascular condition in osteonecrosis.
In patients taking long-term bisphosphonates, it appears that we should
be concerned about possible decreased blood flow during new bone
formation.

Bisphosphonate-induced
Osteonecrosis
Bisphosphonate osteonecrosis is strikingly similar to the “phossy jaws”
found during the 19th century in match, fireworks, and brass industrial
workers who were overexposed to white phosphorous.
 Bisphosphonate osteonecrosis appears as chemically induced osteopetrosis
in which the microcirculation of the bone is decreased until the endpoint of
necrosis is reached.
If the mineral matrix is not absorbed by the osteoclast, new bone growth
and capillary formation will not be stimulated properly; this eventually
leads to acellular and avascular bone.The vasculature in the surrounding
mucosa appears clinically normal and unaffected.
Glucocorticoid osteonecrosis occurs in the long bones but rarely in the
jaws. Radiation osteonecrosis, which clinically presents similar to
bisphosphonate osteonecrosis, occurs in the mandible but is uncommon in
the maxilla because of the high vascularity

Bisphosphonates induced osteonecrosis symptoms can mimic dental or
periodontal disease.
Osteonecrosis was reported only in the maxilla and the mandible—in
alveolar bone—and not in any other bones of the body.
Necrosis was found predominantly in the posterior alveolar regions of the
maxilla and the mandible.
 A pharmacologic explanation of why osteonecrosis is found at these sites
could be that alveolar bone, with constant masticatory functions,
contributes to accelerated drug uptake because its bone turnover rate is 10
times greater than in the tibia.
 Since bisphosphonate decreases normal physiologic bone deposition and
remodeling, the constant force of mastication could cause unrepaired
microfractures, possibly setting the stage for osteonecrosis.

The initial oral lesion seen in a case
of bisphosphonate- associated
necrosis of the jaws is a mucosal
dehiscence, with exposure of the
underlying mandible or maxilla .
 Although the lesion itself is
reportedly quite painful, some
patients have first noted irritation
of adjacent structures, such as the
lateral border of the tongue, due to
constant abrasion from the exposed
bone. A. Initial presentation on left mandible. B. Initial
presentation on right mandible. C. Progress of bone
exposure one year later, showing bone necrosis and
secondary infection
on left mandible after extraction of upper right
third molar and part of fixed bridge. D. Left
mandible one
month before patient’s deathwww.indiandentalacademy.com

Most disturbing about this type of lesion is that it does not respond
well to any known treatment regimen. Surgical debridement results in
more necrotic bone and further deterioration. Cessation of the
bisphosphonate therapy will not improve the situation, probably due
to the persistence of the compound in bone. Even treatment with
hyperbaric oxygen, which is beneficial in treating osteo-
radionecrosis, is of no benefit with bisphosphonate induced bone
exposure

Osteonecrosis Diagnosis
The diagnosis is made using the following criteria:
 Absent or delayed hard and soft tissue healing post-dental trauma, for
example, extraction/implant placement/etc.
Bisphosphonate therapy (primarily IV). Some cases have been reported
with patients on oral alendronate (Fosamax).
Probable systemic condition(s) that alter immune response and delay
wound healing.
Pain although some patients deny any pain symptoms.
 Lack of sensory sensation (with severe and extensive osseous exposure).

Orthodontic Implications
Successful orthodontic treatment depends on osteoclastic activity to allow
tooth movement. Inhibition of tooth movement should be presumed to
occur to a greater degree and sooner with high IV doses than lower oral
doses.
Although the bisphosphonate inhibition of tooth movement was reported
in animals, it was not quantified for any dose or duration of
bisphosphonate treatment in humans.
The accumulated pharmacologic effects of bisphosphonates appear to
affect bones in stages influenced by dose and potency, route of
administration, continuous administration, duration of treatment, a drug
group that specifically binds to bone and is released during turnover,and
degree of turnover in a specific bone.

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.
This is known as bisphosphonate effect accumulation theory (BEAT).
Orthodontic tooth movement causes greater alveolar bone turnover and might
further increase the uptake of bisphosphonates locally.

An ultra structural study Kim T W etal of the effects of
bisphosphonate administration on osteoclastic bone resorption
during relapse of experimentally moved rat molars suggested that
bisphosphonate administration decreases the extent of relapse via a
mechanism involving impairment of the structure and resorptive
functions of osteoclasts.
Effect of Bisphosphonate on tooth movement :-
Orthodontic tooth movement is mediated by a coupling of bone
resorption on the compressed side of the PDL and bone formation on
the stretched side.
The relapse of orthodontically moved teeth is a physiologic response
to force application and is caused mainly by increased mechanical
stress exerted by transseptal fibers.
The presence of bisphosphonates at the site of bone resorption has
been suggested to be essential for the inhibition of osteoclastic
resorption thereby incresing the time of tooth movement.

Anchorage and retentive effects of a bisphosphonate on tooth
movement in rats by Igarashi K etal showed that orthodontic tooth
movement can be inhibited by both systemic and topical administration of
bisphosphonates .Bothanchorage and retentive effects were dose
dependent.
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.

Effects on root resorption :-
Bisphosphonates have a preventive effect on root resorption,this is of great
importance on considering the root resorption, and even loss of the root, that
sometimes occur in patients undergoing orthodontic treatment.
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.
Therefore further studies required before these drugs can be used in clinical
orthodontic therapy

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 proposed 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 depending on
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).www.indiandentalacademy.com

Evaluate treatment plan based on risk group.
If a patient has high risk/high level of osteoclastic inhibition
(IV bisphosphonates)
Avoid orthodontic treatment
Orthodontic treatment should begin only after discussions with the
oncologist, the dentist, and the patient to determine that more benefit
will occur than risk.
Elective surgeries should be avoided (extractions, implants,
periodontal surgeries) after IV bisphosphonates.
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)
Revise your orthodontic treatment plan based on your
assessment of potential risks. Options might include avoiding or
minimizing elective surgery and extractions
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
Informed consent should include all potential risks of
bisphosphonates
Routine dental and periodontal examinations for these patients
are even more important during orthodontic treatment.www.indiandentalacademy.com

Things to remember
If you are taking bisphosphonate tablets you should take them on an empty
stomach. Some people find it easiest to take them first thing in the morning
and wait at least an hour before eating anything or having any milk. This is
because bisphosphonates aren’t absorbed well if you take them with food or
milk
You should aim to drink plenty of fluids when on bisphosphonates - this
will help to protect your kidneys. Ask your doctor or nurse how much fluid
they recommend you to drink each day
Bisphosphonates can interact with other drugs you are taking. This
includes some painkillers such as non-steroidal anti-inflammatory drugs
(NSAIDs) and antibiotics. You should check with your doctor before taking
any new medication
Bisphosphonates could have a harmful effect on a developing baby. You
should not become pregnant or father a child whilst on bisphosphonates.
Discuss contraception with your doctor before you start your treatment if
there is any possibility that you or your partner could become pregnant.

Conclusion
A thorough knowledge about the drugs is mandatory for
dental professionals dealing with patients under orthodontic
treatment.
Bisphosphonate therapy for patients is an important issue in
dentistry.Patients take bisphosphonates for multiple reasons
and, though the incidences of osteonecrosis are rare, patients
should be made aware of the potential risks associated with
the drug during dental treatment.

Increasing our knowledge of bisphosphonates is critical
because these drugs can impede orthodontic treatments and
increase morbidity to the maxilla and the mandible.
Bisphosphonate complications might develop under our direct
observation. As orthodontists, we must be aware of, document,
and report any problems to our medical and dental colleagues
so that the risks and benefits of bisphosphonate treatment can
be fully understood.
The members of our specialty should strengthen their
knowledge, awareness,and communication of these issues and
adhere to the primary principle, “first, do no harm.”

Refrences
Graham J W. Bisphosphonates and Orthodontics:Clinical Implications.
JCO 2006;XL;7:425-428
Zahrowski J. Bisphosphonate treatment: a present orthodontic concern
calling for a proactive approach AJODO 2007;131:311-20.
Igarashi K, Mitani H, Adachi H, Shinoda H. Anchorage and
retentive effects of a bisphosphonate (AHBuBP) on tooth movement in rats.
AJODO1994;106:279-89.
Kim T, Yoshida Y, Yokoya K, Sasaki T.
An ultrastructural study of the effects of bisphosphonate administration on
osteoclastic bone resorption during relapse of experimentally moved rat
molars. AJODO 1999;115:645-53.

Schwarz HC. Bisphosphonate-associated osteonecrosis of jaws. J Oral
Maxillofac Surg 2005;63:1555-6.
Woo S, Hellstein JW, Kalmar JR.
Systemic review: bisphosphonates and osteonecrosis of the jaws. Ann
Intern Med 2006;144:753-61.
Marx, R.E.; Sawatari, Y.; Fortin, M.; and Broumand, V.:
Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the
jaws: Risk factors, recognition, prevention, and treatment, J. Oral
Maxillofac. Surg. 63:1567-1575, 2005.
Triphati K D, Text book of pharmacology 4th
edi.

bisphosphonates and orthodontics clinical implications.

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