Optimizing orthodontic treatment in patients taking bisphosphonates for osteoporosis

CLINICIAN’S CORNER

Optimizing orthodontic treatment in patients

taking bisphosphonates for osteoporosis

James J. Zahrowski

Tustin, Calif

Bisphosphonates have unique pharmacological characteristics unlike those of any other drug group. Millions

of adults take oral bisphosphonates for long-term treatment of osteoporosis and osteopenia; some of these

people will most likely also seek orthodontic treatment. Adverse dental effects from bisphosphonates have

been reported, including decreased tooth movement, impaired bone healing, and osteonecrosis in the man-

dible and the maxilla. Osteonecrosis has been rarely observed after bisphosphonate use for osteoporosis.

However, adverse drug effects might occur more frequently in orthodontic patients, and they would probably

be noted before the end-stage pathology of osteonecrosis. Adverse effects during orthodontic treatment,

including decreased tooth movement, could last for years after the drug therapy is stopped. Successful ortho-

dontic treatment requires optimal bone healing to prevent excessive tooth mobility. Bisphosphonates appear

to have 2 bone elimination rates—a fast elimination of weeks from the bone surface and a slow elimination of

years after incorporation into the bone structure. This article presents methods to clinically and radiographi-

cally monitor orthodontic patients who are taking oral bisphosphonates. Efforts to minimize adverse effects

and optimize orthodontic procedures with physician-approved drug holidays are discussed. The orthodontic

treatment results of 3 patients who received bisphosphonate therapy are reported. (Am J Orthod Dentofacial

Orthop 2009;135:361-74)

isphosphonate (BP) is used for the long-term

treatment of osteoporosis and osteopenia by mil-

lions of adults who might also seek orthodontic

treatment.

1-4

Approximately 1.5 million osteoporotic

fractures occur annually in the United States, with the

incidence projected to rise.

Osteoporotic fractures are

a principal cause of disability and death.

Although

a higher fracture risk is noted in those with osteoporosis

than osteopenia, an estimated 33 million people in the

United States—80% of them women—have osteopenia

with more fracture risk than the normal population.

Af-

ter menopause, decreased estrogen secretion leads to

relatively increased osteoclastic activity and increased

bone resorption.

3,4

The internal cross-links break be-

cause of more resorption in trabecular bone than in

cortical bone.

The destabilized bone structure allows

more fractures to occur in the hip and the lumbar verte-

bral regions.

8,9

Bone density in these regions is usually

measured by dual-energy x-ray absorptiometry.

Osteo-

penia is deﬁned as decreased bone density of 1 to 2.5 SD

below the mean. Osteoporosis is deﬁned as a further de-

crease of bone density more than 2.5 SD below the

mean. Patients with severe osteoporosis and a previous

fragility fracture are at higher risk for future fractures.

Oral BP treatment has been related to a 50% decrease

of bone fractures in the hips and the vertebrae.

Intrave-

nous BP, such as zoledronic acid given yearly or ibandr-

onate given every 3 months, have been recommended

for osteoporosis treatment by increasing compliance

and decreasing fractures up to 70%.

10,11

Oral BP is 1

of the 15 most prescribed drugs in the United States

and a primary long-term osteoporosis treatment that re-

duces morbidity and mortality with few adverse medical

effects.

2,7

The BP pharmacological site of action is in the oste-

oclast, which removes the outer rufﬂed border, inacti-

vates function, and decreases the lifespan of the

cell.

12-14

The drug enters the osteoclast through endo-

cytic vacuoles.

Commonly used BP, containing a nitro-

gen group, primarily inhibits farnesyl pyrophosphate

synthetase and geranylgeranyl pyrophosphatase.

15,16

Enzyme inhibition causes a decrease of proteins respon-

sible for cytoskeletal integrity and intracellular signal-

ing.

12,16

There is some evidence that this drug group

might also inhibit osteoclast precursors and osteoblast

communication with osteoclasts.

15,16

Absorption of

BP through the small intestine is low. Approximately

0.06% of the oral dose reaches the bloodstream as

opposed to 100% when given intravenously.

13,17

Once

the drug is in the bloodstream, approximately 50% is

excreted within hours by the kidneys, and the other

Private practice, Tustin, Calif.

Reprint requests to: James J. Zahrowski, 13372 Newport Ave E, Suite E, Tustin,

CA 92780; e-mail, [email protected].

Submitted, April 2008; revised and accepted, August 2008.

0889-5406/$36.00

doi:10.1016/j.ajodo.2008.08.017

361

half is preferentially bound to the surfaces of high bone

turnover.

Preferential drug binding was documented

by a 3-times higher alendronate concentration in trabec-

ular bone, which has a 3-times greater bone turnover

rate than cortical bone.

Various locations in the body

have different bone repair rates. It was reported that al-

veolar bone has up to a 10-times greater bone turnover

rate than skeletal bones because of the constant mastica-

tory forces.

After BP is incorporated into the bone,

drug elimination occurs slowly and is regulated by the

physiologic rate of bone turnover.

9,17,19

Since high

bone turnover occurs during orthodontic treatment,

more BP might be bound and incorporated around the

teeth than in other bone areas of the body.

After 3 months of oral BP use, bone resorption de-

creased by 50% to75% as measured by osteoclastic sys-

temic bone markers, carbon or nitrogen telopeptide.

After 6 months of oral drug use, bone formation also de-

creased by 50% as measured by an osteoblastic systemic

bone marker, bone-speciﬁc alkaline phosphatase.

The

resultant decrease in bone formation was thought to be

indirectly caused by intercellular osteoclastic mediators

suppressing osteoblastic activity. The systemic bone

markers stabilized at these levels and did not decrease

further after long-time oral BP use.

22,23

One study noted

that nonhealing skeletal fractures occurred after many

years of continuous oral BP use.

Fracture site biopsies

showed a 95% decrease in bone formation, whereas the

systemic marker of bone formation decreased by only

50%. Therefore, systemic bone function tests might

not accurately describe locally decreased bone function

around the teeth caused by BP.

Adverse dental effects of BP were reported to de-

crease tooth movement, impair bone healing, and induce

osteonecrosis in the mandible and the maxilla.

25-27

This

drug group causes decreased tooth movement rapidly

and was reported to interfere with orthodontic re-

sults.

28,29

Optimal tooth movement and bone healing,

which are dependent upon osteoclastic and osteoblas-

tic activity, are important for a successful orthodontic

treatment result. Although BP-induced osteonecrosis

was ﬁrst reported in 2003, similar nonhealing extrac-

tion sites with jaw necroses was reported in 19th cen-

tury factory workers who were overexposed to white

phosphorus.

30,31

BP-induced osteonecrosis is currently

deﬁned as exposed necrotic bone in the mandible or

the maxilla for at least 8 weeks with prior BP use

and no history of radiation treatment to the jaws.

The soft-tissue exposure of necrotic bone usually

was observed after extractions but also was noted

with periodontal disease and periodontal surgery, or

occurred spontaneously over tori or posterior lingual

of the mandible.

Untreatable jaw osteonecrosis

was reported with an incidence of 4% to 10% in

bone cancer patients who received continuous large

intravenous doses of BP, zoledronic acid or pamidro-

nate.

27,33-36

The reported high incidence and severity

of osteonecrosis is probably due to the 12 to 50 times

greater systemic BP dose given to treat bone cancer

than osteoporosis.

37,38

Bone cancers, such as multiple

myeloma or metastatic breast cancer, treated with BP

given intravenously usually contraindicate any ortho-

dontic or elective dental surgery procedures.

25,33

pharmacology is important for the orthodontist to un-

derstand to evaluate adverse drug effects to the bone

around the teeth.

BP STRUCTURE RELATES TO PHARMACOLOGICAL

ACTIVITY

BP has a chemical structure change in which car-

bon, substituted for oxygen in pyrophosphate, is be-

tween 2 phosphates as shown in Figure 1.

Pyrophosphate, rapidly inactivated into 2 phosphates

by tissue alkaline phosphatase, is secreted by the

smooth muscle and can prevent vascular or soft-tissue

calciﬁcation.

BP affects bone regulation because of

the structural carbon change.

9,12

The drug cannot be

metabolized by the tissue or the liver and can only be

eliminated through the kidneys. BP has R1 and R2

groups attached to the carbon; these increase bone af-

ﬁnity and drug potency, respectively (Fig 1). The com-

mon medical uses, bone afﬁnity, potency, and R group

structures of the BP types are shown in Table I.A

greater afﬁnity to human bone was found when a hy-

droxyl group (OH) was present in the R1 group, as

Fig 1. BP structure. Carbon between the phosphate

groups allows no metabolism in the body (pyrophos-

phate contains oxygen between phosphate groups).

Pharmacology of different types depends on R1 and

R2 groups attached to carbon. R1 group increases bind-

ing to bone (calcium), especially when OH is present; R2

group increases potency, especially when nitrogen is

present.

362 Zahrowski

American Journal of Orthodontics and Dentofacial Orthopedics

March 2009

demonstrated by the 15 times stronger afﬁnity of

alendronate to bone than clodronate.

The BP types

used for osteoporosis have strong afﬁnities to bone

with smaller variations, since they all have an OH group

in R1. Alendronate has the strongest afﬁnity to bone,

30% stronger than risedronate or zoledronic acid and

almost 2 times stronger than ibandronate. Since these

drugs have a high afﬁnity to calcium, they are quickly

targeted and bound to the exposed hydroxyapatite of ac-

tively resorbing bone in the body.

When nitrogen was

present in the R2 group, drug potency was in-

creased.

12,13,17,41

Increased potency corresponds to

a smaller amount of the drug needed to suppress osteo-

clastic function. Zoledronic acid is the most potent type

due to a cyclic nitrogen group in R2. The relative sys-

temic effects per dose for the BP types used in osteopo-

rosis are compared in Table II. Higher-potency drug

types are usually given at lower dosages to provide sim-

ilar medical treatment efﬁcacy and fewer adverse ef-

fects. Similar systemic effect doses for alendronate,

risedronate, and ibandronate are noted when comparing

daily dosages. A higher systemic dose is given as the

time between doses is increased. This can be noted

when comparing the increased weekly dose of alendro-

nate or risedronate to the respective daily dose. The

150-mg monthly dose of ibandronate is given at twice

the expected oral dose from a simple calculation of

the daily dose multiplied by 30 days. A larger monthly

dose is needed for effectiveness, probably due to

ibandronate’s lower bone afﬁnity that allows the active

drug on the bone surface to leave more rapidly and be

eliminated. Although this article discusses the entire

BP drug group, the severity of adverse dental effects

might be different for each BP type based on differ-

ences in systemic effective dose, bone afﬁnity, and

other inherent characteristics.

Table I. Comparison of BP types

Common use

Types

Cancer Osteoporosis Pagets, hypercalcemia R1 group*

Bone afﬁnity

† R2 group

‡ Potency

3,17,41

Alendronate -OH 1.5 -(CH2)3-NH2 700

(Fosamax [Merck,

Whitehouse Station,

NY], oral)

Risedronate -OH 1.1

-CH2

2000

(Actonel [Proctor &

Gamble, Cincinnati,

Ohio], oral)

Ibandronate -OH 0.8

-(CH

)

– N – CH

(CH

)

- CH

4000

(Boniva [Roche, Basel,

Switzerland], oral

and IV)

Zoledronic acid -OH 1.1

-CH2 – N

10,000

(Reclast [Novartis, Basel,

Switzerland], IV)

(Zometa [Novartis], IV) X

Pamidronate -OH 1.1 -(CH2)2-NH2 325

(Aredia [Novartis], IV) X

Etidronate -OH 1.0 -CH3 1

(Didronel [Proctor &

Gamble], oral and IV)

Tiludronate -H 0.5

-S CI

(Skelid [Sanoﬁ-Aventis,

Paris, France], oral)

Clodronate -CI 0.1 -CI 10

(Bonefos [Berlex Inc,

Schering, NJ], oral)

IV, Intravenous; Ki, human bone afﬁnity.

*R1 group: hydroxyl (OH) increases binding to bone; †Bone afﬁnity: relative bone afﬁnity compared to etidronate as 1 (etidronate Ki divided by type

Ki); ‡R2 group: nitrogen (N) increases drug potency; xPotency: relative drug potency compared to etidronate as 1.

American Journal of Orthodontics and Dentofacial Orthopedics

Zahrowski 363

Volume 135, Number 3

BP HAS FAST AND SLOW ELIMINATION RATES

FROM BONE

The bone elimination half-lives for BP have been re-

ported over an extremely wide range from several days

for ibandronate to over 10 years for alendronate.

13,17

However, the different methodologies of the elimination

studies are often overlooked. The BP drug group appears

to have 2 bone elimination rates: fast and slow.

13,17,37,42

The short BP half-life was documented by short-

term blood studies of ibandronate (37-157 hours), zole-

dronic acid (146 hours), and risedronate (224-561

hours).

11,13,43,44

Alendronate was observed to have

a similar short half-life when compared with risedronate

over a 30-day period.

The documented short half-lives

for the BP types provide additional information for the

entire drug group regarding bone surface elimination.

By pharmacokinetic principle, drug concentration

would be estimated to decrease 94% after the drug is

discontinued for a time period of 4 half-lives.

Most ac-

tive BP, that is on the bone surface, should be eliminated

rapidly after the drug is stopped for a period of 4 half-

lives. A biphasic bone elimination of alendronate was

reported in rats with approximately 40% of the drug

leaving in 30 days, and the rest leaving at a much slower

rate.

The blood concentration decreased rapidly and

could not be accurately measured 30 days after drug dis-

continuation. A biphasic bone elimination rate was also

established for osteoporosis patients taking alendro-

nate.

Forty percent of alendronate bound to the skele-

ton was rapidly excreted in the urine during a 3-month

period. The rapid elimination rate was interpreted to

be alendronate leaving the bone surfaces before bone in-

corporation. The rest of the alendronate was estimated

to be slowly excreted over decades after bone incorpo-

ration. Therefore, stopping oral BP for 3 months would

appear to decrease the active drug to a minimum level

on the bone surface and in the blood.

A long BP half-life was documented by long-term

urine collections of alendronate and pamidronate.

13,47

It is believed that the BP drug group, once incorporated

in the bone as an inactive drug, would be released

slowly as an active drug during normal bone repair.

8,9,19

Since the active drug release would slow bone turnover,

it would also slow its own elimination from the bone.

This could explain the estimated long drug elimination

half-life of more than 10 years.

The BP, incorporated

into the bone, continued to decrease skeletal fractures

for 5 years after drug discontinuation.

Orthodontic

treatment, as teeth are moved into the BP incorporated

bone, might be adversely affected years after the drug

is stopped.

OSTEONECROSIS OCCURS RARELY AND MIGHT

BE PREVENTABLE

During oral BP treatment for osteoporosis, osteonec-

rosis has been noted rarely and is usually treatable. The

length of continuous oral BP use and type of dental pro-

cedure are important to note. Most osteonecrosis cases

were discovered in patients who had taken oral BP con-

tinuously for more than 3 years and had extractions.

Other factors that increase osteonecrosis risk might be

diabetes, periodontal disease, glucocorticoids, alcohol,

and smoking. No large prospective study has carefully

evaluated the incidence of osteonecrosis after long-

term continuous oral BP treatment for osteoporosis.

Osteonecrosis incidence was ﬁrst reported: 0.7 cases

per 100,000 patient years of drug exposure.

Some

investigators suggested that this incidence was underre-

ported.

26,50,51

Recent reports suggested that the osteo-

necrosis incidence of approximately 1:5000 occurs

after 2 to 3 years of continuous oral BP use with in-

creased incidence after extractions, as shown in Table

III. In a large Australian survey of patients taking weekly

oral alendronate for more than 2 years, an osteonecrosis

Table II. Comparisons of BP types used for osteoporosis treatment

Types

1,10,11,43

Potency

13,17,41

Dose (interval)

1,10,11,43

Systemic absorption

13,17

Relative systemic

effect per dose*

Oral treatment for osteoporosis

Alendronate (Fosamax) 700 10 mg (daily) 0.6% 1

70 mg (weekly) 0.6% 7

Risedronate(Actonel) 2,000 5 mg (daily) 0.6% 1.4

35 mg (weekly) 0.6% 10

Ibandronate (Boniva) 4,000 2.5 mg (daily) 0.6% 1.4

150 mg (monthly) 0.6% 90

Intravenous treatment for osteoporosis

Ibandronate (Boniva) 4,000 3 mg (3 months) 100% 286

Zoledronic acid (Reclast) 10,000 5 mg (12 months) 100% 1190

Higher systemic effect dose is given as dosage interval increased.

*Potency x dose x systemic absorption and compared to alendronate as 1.

364 Zahrowski American Journal of Orthodontics and Dentofacial Orthopedics

March 2009

incidence of 1:2300 to 1:8500 was reported; it increased

up to 1:300 when extractions were performed.

A retro-

spective institutional study reported osteonecrosis from

oral bisphosphonates occurred frequently after extrac-

tions, with a high incidence of 1:20.

This study also re-

ported that no osteonecrosis was found after 4384

extractions in patients never using oral bisphosphonates.

Osteonecrosis has been successfully treated with ne-

crotic bone removal and bone grafting after an oral

drug holiday of 6 months, with the drug restarted 3

months after the surgery.

26,32

Chlorhexidine 0.12%

rinses and appropriate antibiotics were used to help con-

trol secondary infections.

The American Association of Oral Maxillofacial

Surgeons (AAOMS) recommends osteonecrosis preven-

tion through a drug holiday if oral BP has been taken

continuously for more than 3 years or less than 3 years

with glucocorticoids, such as prednisone, as shown in

Table III.

After physician approval, a drug holiday is

requested 3 months before and 3 months after elective

dental surgery. The AAOMS recommendations for os-

teonecrosis prevention were based on successful treat-

ment of BP-induced osteonecrosis in osteoporosis

patients after an oral drug holiday. A drug holiday is

not needed before routine root canal treatment, root scal-

ing, or tooth restorative procedures.

A study of 98 pub-

lished cases of oral BP-induced osteonecrosis found that

50% of the patients were concurrently taking glucocorti-

coids, which might be a contributing factor.

Long-term

glucocorticoids are used to treat chronic inﬂammatory

conditions and might chemically induce osteoporosis,

which is commonly treated with oral BP.

Glucocorti-

coids directly decrease osteoblastic activity and increase

the oral absorption of alendronate by 20% to 44%.

48,53

Most BP-induced necroses commonly seem to in-

volve the bone surrounding the teeth with later progres-

sion into the alveolar bone in the jaws.

BP might also

inhibit normal vascularization at high concentrations

found in bone.

These reports support a theory that

greater adverse effects of BP occur in areas of high

bone repair. An exaggerated cycle of the active BP be-

ing bound and released might decrease cellular bone

function more in high bone-turnover areas than in low

areas.

Nontooth-bearing areas having lower bone

turnover might explain why prospective and retrospec-

tive studies of implant placements have not reported ad-

verse effects from oral BP use.

55,56

However, caution is

needed, since implant failures have been reported after

long oral BP use.

26,57,58

Dental procedures that involve

the bone around the teeth, such as extractions, periodon-

tal surgery, and tooth movement, appear to be more sus-

ceptible to adverse BP effects and are commonly

included in orthodontic treatment plans.

ADVERSE EFFECTS OF INTRAVENOUS BP

The osteonecrosis incidence after long-term BP

given intravenously for osteoporosis treatment is

unknown but presumed to be rare. In a 3-year, dou-

ble-blind study, 3889 women were given 5 mg of zole-

dronic acid yearly for osteoporosis intravenously and

3876 were given a placebo. Two osteonecrosis cases

were found and treated successfully. One osteonecrosis

patient was found with zoledronic acid treatment and

the other with a placebo.

The study’s methodology

contained no routine dental screenings and no com-

ments about prior BP use for the placebo patient.

The osteonecrosis incidence might have increased if

the study had been longer than 3 years, since almost

all osteonecrosis cases from oral BP were noted after

3 years of continuous use.

Although the systemic ef-

fect per dose is much higher from intravenous when

compared with oral usage, the time interval between

doses is longer (Table II). The long dosage interval

Table III. Osteonecrosis incidence and prevention during oral BP treatment for osteoporosis

Osteonecrosis incidence

50,51

(after 2-3 years continuous oral BP use)

No drug holiday Drug holiday

Usually rare, extractions may dramatically

increase incidence

Decreased drug: PDL bone surface and blood

Higher risk with glucocorticoid use, diabetes,

PDL radiographic changes

Less risk of osteoneocrosis,

Optimized bone healing

Osteonecrosis prevention (AAOMS guidelines)

(continuous BP more than 3 years or less than 3 years with glucocorticoid use)

Drug holiday 3 months before and 3 months after elective dental alveolar surgery

Any drug holiday must be done with the knowledge and consent of the prescribing physician

If drug holiday not authorized: osteonecrosis risk explained, usually treated successfully if occurs

No drug holiday needed for routine root canals, root scaling, or restorative procedures

American Journal of Orthodontics and Dentofacial Orthopedics Zahrowski 365

Volume 135, Number 3

should result in a low active drug level retained on the

bone surfaces and allow a more normal cellular func-

tion to return between doses. Until 5- to 10-year stud-

ies with routine dental screenings are performed, both

intravenous and oral BP used for osteoporosis treat-

ment are presumed to have similar rare occurrences

of osteonecrosis.

Orthodontists should proceed with caution regard-

ing decreased tooth movement and bone formation after

intermittent intravenous BP administration for osteopo-

rosis with ibandronate (Boniva) and zoledronic acid

(Reclast). Ibandronate is more frequently administered

probably because of lower bone afﬁnity and effective

systemic dose than zoledronic acid (Tables I and II).

Higher effective systemic doses noted from intravenous

than from oral administration could greatly inhibit tooth

movement (Table II). During orthodontic treatment,

concurrent intravenous BP could highly elevate the

bone surface levels around teeth and lead to more

drug incorporation.This might limit present and future

tooth movement more rapidly and profoundly. Ibandro-

nate at the 3-mg dose given intravenously every 3

months and perhaps the monthly 150-mg oral dose

would lead to higher initial bone surface levels that

might remain elevated enough to slow tooth movement

until the next dose is given. Zoledronic acid, at a 5-mg

dose intravenously every 12 months, should immedi-

ately increase the lamina dura surface level but decrease

3 months after the initial dose. Intuitively, a limited or-

thodontic treatment plan might be successful if started 3

to 6 months after the previous dose and ﬁnished before

the next dose is given. Since 1 dose of zoledronic acid

sustains a 12-month reduction of bone turnover, it is un-

certain how much tooth movement or bone healing

would occur between doses. A small amount of a highly

potent BP, remaining on the bone surface or released

from the bone could be enough to interfere with ortho-

dontic treatment.

RADIOGRAPHIC CHANGES: SIGN OF DECREASED

BONE FUNCTION DURING BP USE

A radiographic hyper-mineralized area might sig-

nify osteoclastic activity that has been dramatically de-

creased from BP use.

The sclerotic areas might not

have enough osteoclastic activity to remove diseased

bone and form proper vascular structures. BP slows

bone formation, but mineralization is unaffected.

19,21

Sclerosis was reported as a beginning BP toxicity in

alveolar bone before osteonecrosis.

26,33,60

Sclerotic

bone was observed when no orthodontic tooth move-

ment occurred during BP use.

The sclerotic areas

can appear around teeth or obscure the periodontal liga-

ment (PDL) space.

A widened PDL space might be

a sign of decreased bone formation before osteonecro-

sis.

The lamina dura around the PDL and the PDL

space should be closely examined in initial and progress

radiographs, especially in the mandibular molar regions.

The bone surrounding the mandibular molars might be

more susceptible to adverse BP effects because posterior

occlusal forces cause higher bone turnover, and the man-

dible has a lower vascular supply than the maxilla.

26,27

After long-term continuous BP use, radiographi-

cally obscured PDL space and sclerosis of the lamina

dura were noted in the left posterior region, signifying

possible local BP toxicity (Fig 2). Osteonecrosis was

observed after the extraction of a painful mandibular

molar on the contralateral side.

PATIENT 1: COMPROMISED NONEXTRACTION

RESULT WITH ORAL BP USE

Oral BP use during orthodontic treatment would

sustain a high blood concentration with presumably

more active drug bound and incorporated into the

bone surrounding teeth. Progressively slower tooth

movement could occur with continued BP administra-

tion. Slow tooth movement can continue years after

stopping the drug.

A 60-year-old woman, completing nonextraction,

nonsurgical orthodontic treatment that lasted 4.5 years

with compromised results, requested a second opinion

(Fig 3). Her concerns were uneven posterior occlusion,

heavy occlusal contact on anterior bridge, minor poste-

rior spacing, slow tooth movement, long treatment time,

and reports of BP inducing osteonecrosis. Before her or-

thodontic treatment, she had a signiﬁcant right posterior

open bite and used alendronate for osteoporosis for 18

months. No signs or symptoms of osteonecrosis were

apparent from a clinical exam or history. The beginning

panoramic radiograph showed mild sclerosis within

normal limits on the mandibular right second molar,

Fig 2. Obscured PDL with sclerosis might signify early

BP toxicity. After long-term continuous BP use, osteo-

necrosis presented on the contralateral side following

a molor extraction.

366 Zahrowski

American Journal of Orthodontics and Dentofacial Orthopedics

March 2009

a small left condyle, and a periodontal defect between

the maxillary left ﬁrst and second molars (Fig 3, A).

After 2 years of orthodontic treatment and concurrent

alendronate use, pronounced sclerotic bone around the

teeth and widened PDL spaces were observed, espe-

cially in the mandible (Fig 3, B). The physician, un-

aware of the changed radiographic signs, stopped

alendronate and started teriparatide treatment to achieve

higher bone density for her osteoporosis treatment. Af-

ter 3.5 years of orthodontic treatment, widened PDL

spaces and diffuse sclerotic areas were present (Fig 3,

C). After 4.5 years of orthodontic treatment, diffuse

sclerosis and widened PDL spaces were present after

alendronate was stopped for 2.5 years (Fig 3, D). Ortho-

dontic treatment was discontinued by the orthodontist

because of decreased tooth movement and fear of osteo-

necrosis. No root resorption was noted when comparing

the initial and ﬁnal periapical radiographs.

PATIENT 2: COMPROMISED EXTRACTION RESULT

WITH CONCURRENT ORAL BP

During orthodontic extraction treatment, BP could

incorporate in the extraction site and around the teeth

being moved. Root translation into the extraction site

might be slowed after stopping the drug. Decreased

bone formation and excessive tooth mobility can

occur.

A 50-year-old woman came with a Class II (3 mm

left molar) malocclusion, 3 missing ﬁrst premolars,

moderate mandibular incisor crowding, lower midline

to the right, periodontal bone loss, and no tooth mobil-

ity (Fig 4). After periodontal treatment, comprehensive

orthodontic treatment was started with extraction of

the remaining mandibular left ﬁrst premolar. Ortho-

dontic space closure was extremely slow. The patient

had started taking alendronate approximately 6 months

before the extraction and stopped 12 months later be-

cause of esophagitis, a common adverse side effect.

She did not report alendronate use in her medical his-

tory because she did not believe it was an orthodontic

concern. Space closure was difﬁcult, and divergent

roots were noted in the extraction site (Fig 4, B).

Less inhibition of tooth movement was noted after

the alendronate was discontinued for 6 months. The or-

thodontic appliances were repositioned to obtain paral-

lel roots. After 7 months, little root movement

occurred and a hyper-mineralized area was observed

within the extraction site (Fig 4, C and D). Alendro-

nate use had been stopped for 13 months. Excessive

mobility and widened PDL spaces were noted. No

traumatic occlusion or change in periodontal status

was present. Orthodontic movement of the incisors

Fig 3. Patient 1: 60-year-old woman requested a second

opinion after compromised nonextraction result with con-

current BP use. A, Initial panoramic radiograph shows peri-

odontal bone loss between the maxillary left ﬁrst and

second molars and a small left condyle. Prior continuous

BP use of 18 months. Sclerosis in mandibular region is

within normal limits. B, Profound sclerotic areas (greater

in the mandible) surrounding the PDL and widened PDL

spaces are present after 2 years of orthodontic treatment

and concurrent BP use (3.5 years total). C, Diffuse sclerosis

and widened PDL spaces are present after 3.5 years of or-

thodontic treatment. BP was discontinued 18 months ear-

lier. D, Diffuse sclerosis and widened PDL spaces are noted

after 4.5 years of orthodontic treatment. Decreased move-

ment was noted after BP was discontinued 2.5 years ago.

American Journal of Orthodontics and Dentofacial Orthopedics Zahrowski 367

Volume 135, Number 3

was difﬁcult, even though there was mobility. Slow

tooth movement, mandibular incisor mobility, and

compromised parallel roots were observed throughout

the orthodontic treatment.

PATIENT 3: OPTIMIZED EXTRACTION RESULT

WITH AN ORAL BP HOLIDAY

After stopping oral BP for 3 months, a minimum ac-

tive drug level should be present on bone surfaces and in

the blood. A BP holiday throughout orthodontic treat-

ment should sustain a low drug level with less drug in-

corporation into the bone surrounding the teeth.

A 74-year-old woman presented with a Class I oc-

clusion, severe periodontal bone loss, routine periodon-

tal maintenance, severe mandibular incisor crowding,

and a recently fractured mandibular left central incisor

that was clinically unrestorable (Fig 5). She had been

taking oral alendronate continuously for 3 years. Her

intraoral examination was normal, without tooth pain

or exposed necrotic bone. An orthodontic treatment

plan was requested before further dental treatment.

The beginning occlusal photograph showed the frac-

tured incisor temporarily bonded (Fig 5, A). The initial

panoramic radiograph showed mild sclerosis around the

mandibular molars (Fig 5, B). The furcal radiolucency

of the mandibular right ﬁrst molar was under periodon-

tal observation and present before alendronate use. The

initial mandibular anterior periapical radiographs

showed obscured PDL spaces (Fig 5, C). Continuous

alendronate use for 3 years and the obscured PDL

were interpreted as possible decreased bone function.

An osteonecrosis risk was noted for the planned incisor

extraction. Since there were no signs of infection, im-

mediate extraction was thought to be unnecessary. An

immediate temporary root canal was deemed unneces-

sary because of the obliterated root canal. The physi-

cian stopped the alendronate for 3 months before the

incisor extraction according to the AAOMS oral BP

prevention guidelines (Table III). The physician de-

cided that the bone density goal was reached, and no in-

creased patient morbidity was expected during the

extended drug holiday throughout orthodontic treat-

ment. After evaluation of the orthodontic records, lim-

ited braces were placed between the mandibular ﬁrst

premolars after consideration of a functional posterior

occlusion, severe periodontal bone loss, age, and the pa-

tient’s request not to treat the maxillary incisors. The

limited orthodontic treatment was successful with nor-

mal extraction healing, space closure, and acceptable

parallel roots within 14 months. Acceptable parallel

roots, although not ideal, were somewhat slow to

Fig 4. Patient 2: compromised extraction result with

concurrent oral BP therapy. A, Initial panoramic radio-

graph of 50-year-old woman. BP use started 6 months

prior to extraction of left mandibular bicuspid and ortho-

dontic treatment. B, Slow space closure and divergent

roots are noted in extraction site at 12 months of treat-

ment. Mandibular incisors had excessive mobility, in-

creased PDL spaces and decreased movement. BP

was discontinued 6 months prior (12 months total use).

C, Nonparallel roots in extraction site after brace reposi-

tioning (7 months prior) is noted at 19 months of treat-

ment. Incisor mobility and increased PDL spaces still

present. D, Sclerotic area is noted within the extraction

site at 19 months of treatment.

368 Zahrowski

American Journal of Orthodontics and Dentofacial Orthopedics

March 2009

obtain. The ﬁnal photograph showed successful align-

ment and space closure (Fig 5, D). Debonding of the

ﬁxed retainer was noted and repaired. The ﬁnal pano-

ramic radiograph showed no sclerotic changes, PDL

spaces within normal limits, and mild root resorption

on lower central incisor (Fig 5, E). The ﬁnal mandibular

incisor periapical radiographs showed mild sclerosis

and PDL spaces. No mobility was noted on the mandib-

ular incisors. Mild root resorption was noted on the

mandibular incisors. The patient was pleased with the

limited extraction treatment result after prior counsel-

ing about possible adverse effects. The alendronate

was planned to be restarted by the physician after the

orthodontic treatment with no expected adverse dental

effects. A bonded retainer was used, although BP has

been reported to help decrease orthodontic relapse.

The general dentist and the periodontist were asked to

monitor for future radiographic signs after 3 years of

continued alendronate use.

DISCUSSION

The orthodontic treatment in patient 1 could have

been stopped at 2 years after excessive sclerosis was

Fig 5. Patient 3: optimized extraction result with an oral BP holiday. A, Initial mandibular occlusal

photograph shows the fractured unrestorable left central incisor. B, Initial panoramic radiograph

shows mild sclerosis and severe periodontal bone loss. Patient had taken alendronate for 3 years.

C, Initial mandibular incisor periapical radiograph. Obscured PDL is a possible sign of decreased

bone function; the obliterated root canals are from age. D, Final occlusal photograph. The patient’s

physician authorized a drug holiday 3 months before and during orthodontic treatment. E, Final pan-

oramic radiograph shows no sclerotic changes and acceptable parallel roots. This limited extraction

treatment was successful in 14 months. F , Final lower incisor periapical radiograph shows PDL

spaces and sclerosis within normal limits. Mild root resorption is noted.

American Journal of Orthodontics and Dentofacial Orthopedics Zahrowski 369

Volume 135, Number 3

noted around the PDL, since little tooth movement

would be anticipated (Fig 3, B). An osteonecrosis risk

was present after 3 years of continuous alendronate

use and a changed radiographic sign denoting possible

local drug toxicity. Higher osteonecrosis risk and less

bone healing would be expected if extractions or peri-

odontal surgery had been performed.

This was impor-

tant, since a periodontal defect was noted between the

left ﬁrst and second molars. After alendronate was

stopped for 3 to 6 months, the osteonecrosis risk should

have decreased closer to a normal range.

26,32

After the

BP is stopped for 3-6 months, a consideration to con-

tinue orthodontics can be made if clinical and radio-

graphic signs begin to decrease. The length of

orthodontic continuation is a clinical judgement based

on the occlusal improvement that can be achieved. Mi-

nor tooth movement can usually be accomplished, how-

ever major tooth movement might be slowed for years

without normal bone healing, especially if sclerosis is

still present (Fig 3, C and D). Ideally, initiating ortho-

dontic treatment in patient 1 could have been delayed

until 3 months after the physician discontinued the

alendronate and chose an alternate osteoperosis treat-

ment, teriparatide. Teriparatide, a recombinant parathy-

roid hormone, causes more bone formation by

increasing osteoblastic activity. Animal experiments

have shown that parathyroid hormone reverses BP de-

pression of osteoclastic activity.

Teriparatide was

used to treat a rare osteonecrosis case that did not heal

after a 6-month oral BP holiday.

Since teriparatide in-

creases osteoclastic activity, the osteonecrosis risk

should decrease, and orthodontic tooth movement

should increase. In this case, tooth movement continued

to be inhibited from excessive bone incorporation of BP

during the concurrent drug use with orthodontic treat-

ment. Although the sclerosis appeared to be decreasing,

it was observable years after the alendronate was

stopped (Fig 3, C and D). Sclerosis might have a variable

duration, since, in another patient, the sclerosis disap-

peared within a year after the alendronate was stopped.

Concurrent BP use during orthodontic extractions

allows the drug to integrate into the healing bone. Ex-

traction site closure would cause active BP release

from bone resorption, decrease osteoclastic function,

and inhibit further tooth movement. The incorporated

BP might stay in the extraction site for years after

drug is discontinued and continue to slow tooth move-

ment. Slow tooth movement and nonparallel roots in

the extraction site with concurrent BP use has been re-

ported.

Hyper-mineralized lines were observed after

tooth extractions with concurrent BP use.

26,60

Hyper-

mineralized brittle bones were found in children given

long-term BP.

In patient 2, the hyper-mineralized ex-

traction site might signify decreased bone formation

from BP that was not sufﬁcient to affect healing (Fig

4, D). Inhibited movement, excessive mobility, and in-

creased PDL spaces were noted during and after space

closure. The BP, bound and incorporated into bone,

could have decreased bone formation and inhibited

new tooth movement even after the drug was stopped.

A 95% decrease in bone formation was reported after

alendronate use.

Widened PDL spaces were noted as

a possible local sign of BP toxicity.

Subnormal bone

formation, a decrease of 75% to 95%, would presum-

ably occur sooner and more frequently than an end-

stage necrosis or no bone formation. Detection of early

warning signs can be beneﬁcial to provide better ortho-

dontic care and prevent end-stage pathology in patients

taking oral BP.

A drug holiday was used in patient 3 to decrease the

osteonecrosis risk before extraction. If the physician

had decided not to stop the alendronate, the oral surgeon

would have informed the patient of the osteonecrosis

risk. Without a drug holiday, compromised extraction

space closure would have been expected. In this case,

the extraction site was closed satisfactorily. Orthodontic

treatment was optimized by sustaining minimum BP

concentrations on the bone surface and in blood. Mild

root resorption was noted after orthodontic treatment.

BP has been shown to decrease root resorption.

Since

the active drug on the bone surface would decrease after

a drug holiday, the pharmacological protection against

root resorption should also decrease. Even though

a drug holiday might optimize orthodontic treatment,

tooth movement still might not be ideal with extended

oral BP use. Longer use will cause more BP to incorpo-

rate in trabecular bone and remain for many years. Slow

drug release from the skeleton into the bloodstream

would allow more BP to bind during tooth movement.

Drug accumulation can be signiﬁcant in patients who

have been taking oral BP for long periods. It has been

estimated that 25% of a daily dose is released from

the skeleton daily after 10 years of continuous oral ad-

ministration.

BP might also decrease the activity of os-

teoclastic progenitor cells that could contribute to long-

term adverse effects.

16,65

Research is needed to under-

stand the long-term adverse effects of BP in orthodon-

tics.

An orthodontic screening should ask about prior BP

use. A detailed history is needed to establish the speciﬁc

oral or intravenous BP preparations, the duration of use,

and the medical purpose of treatment (osteopenia, oste-

oporosis, or severe osteoporosis with prior fragility frac-

tures). Patients with severe osteoporosis might have

a greater skeletal fracture risk during a drug holiday.

A notation should be made of any patient given

370 Zahrowski American Journal of Orthodontics and Dentofacial Orthopedics

March 2009

intravenous BP (zoledronic acid or pamidronate) for

cancer treatment, since orthodontic or elective dental

surgery should be contraindicated, and drug holidays

do not apply.

25,27,33

Intravenous zoledronic acid is

used to treat both osteoporosis and cancer patients by

changing the time intervals between doses. Zoledronic

acid (Reclast), 5 mg intravenously, is given every 12

months for osteoporosis treatment.

Zoledronic acid

(Zometa), 4 mg intravenously, is given every 3 to 4

weeks for bone cancer treatment.

Bone cancer treat-

ment requires frequent administration of zoledronic

acid to sustain high surface bone levels to limit the can-

cer’s detrimental effect on skeletal bones.

The suggested guidelines, shown in Table IV, are to

optimize orthodontic treatment through appropriate

drug holidays and monitor adverse dental effects during

oral BP treatment of osteoporosis. The guidelines do not

guarantee ideal orthodontic results but should lessen

nonideal results and minimize adverse effects with sound

clinical treatment plans and continued patient monitor-

ing. The guidelines are not meant to be the standard of

care and should be reevaluated as future studies dictate.

The orthodontist should have the patient read and sign

the American Association of Orthodontists’ informed

consent for BP before orthodontic treatment. Changing

clinical and radiographic signs should be carefully mon-

itored especially prior to a drug holiday, since they might

suggest decreased alveolar bone function and early local

drug toxicity. If positive signs occur, orthodontic treat-

ment might need to be discontinued, even if treatment

goals are not achieved. Clinical monitoring should in-

clude changes in decreased movement and increased mo-

bility. Radiographic monitoring should include changes

of sclerotic or radiolucent bone surrounding teeth. Ra-

diographic changes can be caused by other pathologies,

such as infection, prior accidents, periodontal disease,

or occlusal trauma. Careful evaluation of trabecular var-

iations, lamina dura, and PDL space in routine orthodon-

tic patients will give proper comparisons of radiographic

changes caused by BP use. AAOMS osteonecrosis pre-

vention should be considered for any extraction or peri-

odontal surgery planned in an area of decreased bone

function. After 2 to 3 years of oral BP administration,

the differential diagnosis of tooth pain should include os-

teonecrosis. If routine dental procedures, such as root ca-

nal therapy or periodontal scaling, do not relieve

symptoms, then osteonecrosis should be considered

strongly in the differential diagnosis.

The orthodontist

should not act unilaterally if any adverse drug effects are

observed. The physician should be informed of any

changed clinical or radiographic signs that indicate

a BP drug holiday may be of value to help orthodontic

treatment or decrease osteonecrosis risk.

Radiographic signs are not diagnostic for osteonec-

rosis but can suggest a higher risk. The clinical osteo-

necrosis deﬁnition, requiring tissue exposure of

necrotic bone, might be a late diagnosis. Osteonecrosis

has been reported before clinical signs of exposed

Table IV. Suggested orthodontic optimization guidelines during BP treatment for osteoporosis

Drug holiday 3 months before and during orthodontic tooth movement

(decreases and maintains low active drug level: blood and PDL bone surfaces)

No drug holiday Drug holiday

Orthodontic risks

Progressively slower tooth movement Closer to normal range

More tooth mobility

Teeth less likely to move in future

Orthodontic treatment suggestions

Consider: delay untill drug stopped or alternative drug Optimized treatment

(especially extraction cases)

Consider: limited, nonextraction cases with caution

BP effect accumulates with continued use Long prior BP use might

BP bone incorporation might limit future movement slow tooth movement after holiday

Monitoring signs: BP decreased bone function

Clinical signs: slow movement, excessive mobility

Radiographic signs: sclerosis around teeth, obscured PDL, or excessive PDL space

(Rule out trauma, infection, periodontal causes, and normal bone variations)

If signs present, consider careful monitoring, drug holiday, and delay or discontinue orthodontics

The suggested guidelines do not guarantee ideal results but are meant to lessen nonideal results

with sound orthodontic treatment plans and continuous monitoring for adverse effects.

Drug holiday must be done with the knowledge and consent of the prescribing physician

American Journal of Orthodontics and Dentofacial Orthopedics

Zahrowski 371

Volume 135, Number 3

necrotic bone.

Magnetic resonance imaging (MRI)

has shown all BP-induced osteonecrosis lesions before

they were clinically present.

MRI found all necrotic

bone lesions from other causes better than bone scans

or computerized tomography when compared with his-

tologic diagnosis in the hip, knee, ankle, and shoulder.

MRI should be considered for early recognition of os-

teonecrosis in the alveolar bone. MRI might have signif-

icant value, since histologic diagnosis cannot be made

in a suspected BP-induced osteonecrosis for fear of

worsening the situation.

The successful clinical outcome of osteonecrosis

treatment from oral BP has been reported to be related

to a serum C telopeptide level (CTX) level when it is

greater than 150 ng per milliliter.

The CTX level, a sys-

temic osteoclastic bone marker, is obtained from a fast-

ing, early-morning blood draw. The use of the CTX is

controversial, since it measures systemic osteoclastic ac-

tivity from the entire skeleton and does not speciﬁcally

measure the local osteoclastic function in the alveolar

bone. However, the CTX level might be a sensitive mea-

sure of altered bone function caused from the active drug

residing on the bone surfaces. Although controversial,

the CTX level can be considered after a 3- to 6-month

drug holiday to conﬁrm that systemic osteoclastic func-

tion is normal before major dental surgical procedures

when BP was taken continuously for more than 5 years.

Ideally, the orthodontist should contact the prescrib-

ing physician to discuss the planned orthodontic proce-

dure, expected risks, and possible optimization with

a drug holiday. Optimizing orthodontic treatment after

BP use has different requirements than osteonecrosis

prevention (Tables III and IV). Two bone elimination

rates have been reported for the BP drug group. A

3-month drug holiday should lower the active drug con-

centration in the blood and on the bone surfaces around

the teeth to lower the risk of osteonecrosis. An extended

BP holiday during orthodontic treatment should sustain

low active drug levels, lessen drug incorporation sur-

rounding teeth, and optimize tooth movement and

bone healing. During tooth movement, bone turnover

will slowly release any previously incorporated inactive

drug as an active drug. BP incorporated in the bone,

which can remain for many years, should be minimized

in areas where teeth are planned to be moved.

The patient’s treatment goal for osteoporosis might

have been reached, and the physician could decide that

no further oral BP is needed during orthodontic treat-

ment. A randomized, double-blind, multicenter study

of 6459 patients concluded that there was no difference

in the 10-year fracture rate comparing a group taking

alendronate for 5 years with another group taking the

drug continuously for 10 years.

However, it was

concluded that high-risk vertebral fracture patients can

beneﬁt from longer 10-year treatment.

An alternate osteoporosis treatment can be started

by the physician because the treatment goal has not

been reached. It is the physician’s responsibility to sug-

gest alternative osteoporosis treatments, even though

alternate medications might have fewer adverse dental

effects. Alternate treatments such as raloxifene, a selec-

tive estrogen receptor modulator, and estrogen both

have short half-lives with no bone accumulation, and

should affect tooth movement less than BP. However,

alternate drugs could be less effective for osteoporosis.

Treatment alternatives can also have a greater incidence

of serious adverse medical effects.

Estrogen can in-

crease the risk of breast cancer, deep venous thrombo-

sis, and stroke. Raloxifene might increase the risk of

deep venous thrombosis and stroke. Teriparatide is an

effective treatment for vertebral osteoporosis with

shortcomings of high expense, daily subcutaneous in-

jections, duration of treatment not to exceed 2 years,

and another osteoporosis medication needed after 2

years to retain the increased bone density.

It is not appropriate for all patients to have a BP hol-

iday, and the physician might decide that the fracture

risk is too high. The orthodontist can consider not treat-

ing or delaying treatment, especially in elective extrac-

tion patients, until the BP can be stopped or an

alternative medication is appropriate. A consideration

to treat limited, nonextraction patients could be made

with the following precautions. Concurrent BP use

might cause drug accumulation and progressively

slower tooth movement. Slow tooth movement can con-

tinue for years after the drug is discontinued. Orthodon-

tic treatment might have to be discontinued before the

treatment goals have been accomplished. No patient

should stop oral BP medication without the knowledge

and consent of the primary prescribing physician be-

cause bone density might not have risen sufﬁciently to

prevent hip and vertebral fractures. Orthodontists

should understand that prevention of hip or vertebral

fractures takes priority over an elective orthodontic pro-

cedure. Physicians should understand that the patient’s

desired orthodontic result might not be achieved if BP

is continued, especially if the medication is not cur-

rently beneﬁcial. After discussing the medical and or-

thodontic risks and beneﬁts, a mutual decision can be

made in the patient’s best interest.

CONCLUSIONS

This article was written to begin parameters to min-

imize adverse effects and optimize orthodontic treat-

ment in the millions of patients taking oral BP for

372 Zahrowski American Journal of Orthodontics and Dentofacial Orthopedics

March 2009

osteoporosis. Orthodontists clearly need to understand

the pharmacology and adverse effects of this unique

drug group to evaluate early warning signs of decreased

bone function before progression to necrosis. Tooth

movement, tooth mobility, and radiographic changes

of the lamina dura and the PDL spaces need to be eval-

uated and monitored in patients taking oral BP. This

drug group has many medical beneﬁts, and the in-

creased orthodontic risks might be small compared

with the increased medical risks if the medication is

stopped. No patient should discontinue BP without the

knowledge and consent of the primary prescribing phy-

sician. Osteonecrosis occurs rarely during BP treatment

for osteoporosis, and the AAOMS guidelines for osteo-

necrosis prevention and treatment should be reviewed.

Ideally, the orthodontist and the physician should dis-

cuss the patient’s risks and beneﬁts of BP treatment ac-

cording to the severity of the osteoporosis, the projected

risks to orthodontic procedures, and the appropriateness

of a drug holiday to optimize orthodontic treatment and

minimize adverse dental effects.

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