Int. J. Oral Maxillofac. Surg.

2006; 35: 588593

doi:10.1016/j.ijom.2006.02.022, available online at http://www.sciencedirect.com

Leading Clinical Paper

Oral Medicine/Therapeutics

Bisphosphonate-induced I. Dimitrakopoulos, C. Magopoulos,

D. Karakasis
Department of Oral and Maxillofacial Surgery,

avascular osteonecrosis of the Aristotle University of Thessaloniki, Greece

jaws: a clinical report of 11

cases
I. Dimitrakopoulos, C. Magopoulos, D. Karakasis: Bisphosphonate-induced
avascular osteonecrosis of the jaws: a clinical report of 11 cases. Int. J. Oral
Maxillofac. Surg. 2006; 35: 588593. # 2006 International Association of Oral and
Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Abstract. Bisphosphonates are compounds used in the treatment of various metabolic

and malignant bone diseases. In the last 2 years there has been a significant increase
in referrals to the Department of Oral and Maxillofacial Surgery of patients
with exposed necrotic jaw bone, diagnosed elsewhere as chronic refractory
osteomyelitis of jaws, mostly after several teeth extractions. The only clinical
feature in common for all the patients was the use of bisphosphonates in the
treatment of bone diseases.
A retrospective study was performed of 11 patients with necrotic bone lesions of
the jaws of various extents referred to this Department from July 2003 to November
2004. The management of the patients included cessation of bisphosphonate therapy
for 28 months and various surgical restorative procedures thereafter.
Four patients (36%) presented with maxillary bone involvement, 6 (55%) had
mandibular bone necrosis and 1 (9%) presented with necrosis at 3 quadrants. All
patients had received bisphosphonate therapy for 6 months to 5 years. Biopsies from
the necrotic lesions revealed no metastatic disease. One patient who was removed
from bisphosphonate therapy for 8 months recovered completely, one other who
was not removed from bisphosphonate therapy relapsed and for all the others, with
cessation of bisphosphonate therapy for 26 months, the results were inconsistent.
A new complication of bisphosphonate therapy administration, i.e. osteonecrosis
Key words: jaws osteonecrosis; bisphospho-
of jaws, seems to be developing. The improved results after cessation of the nates; bone metastases; fibrous dysplasia.
medication should make clinicians reconsider the merits of the rampant use of
bisphosphonates, while further investigation is needed to completely elucidate this Accepted for publication 27 February 2006
complication. Available online 9 May 2006

The bisphosphonates are synthetic com- porosis, Pagets disease, hypercalcaemia dysplasia but they are still under investi-
pounds developed over the past 3 decades of malignancy and bone pain. Their effi- gation. They are characterized by 2 CP
and used in the treatment of many skeletal cacy has recently been extended to osteo- bonds on a single carbon atom (PCP)
disorders such as bone metastases, osteo- genesis imperfecta and to fibrous with a great number of possible variations,

0901-5027/070588 + 06 $30.00/0 # 2006 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
 Bisphosphonate-induced avascular osteonecrosis of the jaws 589

and are analogues of inorganic pyropho- Toxicological animal studies have sphonates, following the oncologists
sphate (POP). revealed little toxicity, which is probably guidelines, seem to be prevailing.
The biological and clinical potency of due to the low serum concentration of This article presents the clinical evalua-
bisphosphonates vary greatly due to their bisphosphonates and rapid affinity and tion of this recently described complica-
structural variety. Generally they are accumulation to the bone matrix. There tion of the use of bisphosphonates,
divided into 2 main classes with the dif- have been a few reported gastrointestinal previously called drug-induced avascular
ference between them a function of the complications such as gastric and oeso- osteonecrosis13. A therapeutic protocol is
moieties attached to the geminal carbon at phageal erosions and ulcerations and cases suggested for these patients and in the
the R2 side chain which can vary in size of renal failure and acute tubular necro- sections that follow the mechanism that
and complexity. This is related to the sis4. The mechanism that leads to these leads to this complication is discussed.
presence or absence of a nitrogen atom complications is controversial and is still
located in the R2 group. Those that contain an issue for investigation.
nitrogen, and are the most potent, are In the last 2 years there has been an Patients and methods
referred to as N-BPs and are represented increased referral of patients with exposed From July 2003 to October 2004, 11
by aledronate, ibandronate, incadronate, necrotic jaw bone, diagnosed elsewhere as patients were referred to this department,
olpadronate, pamidronate, risedronate chronic refractory osteomyelitis of jaws diagnosed with refractory osteomyelitis of
and zoledronate, while the non-N-BPs mostly after several teeth extractions. the jaws subsequent to their main oncolo-
are mainly clodronate, etidronate and tilu- Most of the patients had a natural history gical history of one of the following dis-
dronate6,19. of malignancy and the only thing in com- eases: multiple myeloma (5 cases),
The main pharmacological effect of mon was the long-term, intravenous prostate cancer (2 cases), breast cancer
bisphosphonates is the inhibition of bone administration of bisphosphonates. The (1 case with concomitant osteoporosis),
resorption, mediated by a decreased func- current knowledge regarding the inci- neuroendocrine cancer (1 case), lung can-
tion of osteoclasts, while other effects like dence of this condition is quite limited cer (1 case) and fibrous dysplasia (1 case)
inhibition of calcification in the treatment and just recently established. In a review (Table 1). In all cases multiple (metastatic
of hypercalcaemia of malignancy and of 36 patients13, 81% presented with pain- or not) osteolytic bone lesions were evi-
reduction of inflammatory reaction in ful exposed avascular bone in the mand- denced by radiographic or nuclear scan
the joints in the treatment of arthritis are ible, 14% in the maxilla and 5% in both the evaluation. The mean patient age at the
of secondary importance. mandible and the maxilla. Teeth extrac- time of presentation was 61 years, with a
The exact mechanism of action of tions are stated to be the main cause of the range of 4776 years. The sex ratio was
bisphosphonates is still a matter of inves- exposed non-healing bone. In addition, a 1:1.2 (5 males and 6 females). In all cases
tigation and variance but undoubtedly they review of 63 cases of jaws osteonecrosis the typical presenting symptoms were
are accumulated mostly in bone matrix associated with the use of bisphospho- localized swelling and pain with exposed
and especially under osteoclasts. This is nates, demonstrates a quite high incidence bone either at the maxilla or at the mand-
the main reason for the primary effect of of maxillary involvement (24 of 63 ible and in 2 cases at more than one
bisphosphonates on bone surface and in patients) and teeth extractions as well as quadrant. In most of the patients the
osteolytic lesions where the number of denture trauma, as the main stimulative exposed bone was subsequent to non-heal-
osteoclasts is increased. They are depos- cause20. There is, as yet, no well-docu- ing extraction sockets while in 1 patient it
ited rapidly in bone within 2448 h and are mented protocol for the preferred method was the result of a chronic denture trauma
almost non-metabolized while their serum of treatment. Recently, minimally inva- and in another 3 it was a spontaneous
half-life is quite brief and serum concen- sive procedures have been suggested, procedure (Table 1).
trations are low8. Unlike the unstable nat- such as administration of antibiotics along All of the patients were treated else-
ure of POP bonds, the PCP structure with 0.12% clorohexidine antiseptic where for chronic refractory osteomyeli-
of bisphosphonates is highly resistant to mouthwash, without resolution of the tis. The treatment included nearly all the
hydrolysis under acid conditions or by exposed bone14,23. Several other recom- current therapeutic protocols for osteo-
pyrophosphatases. mendations for the surgical treatment of myelitis with conservative (culture, anti-
In addition, less is known about the side this entity have been made with good biotics and hyperbaric oxygen) and
effects and dangers of long-term use of results1,7,11. Conservative treatment of surgical (debridementsequestrectomy)
therapeutic doses of bisphosphonates. osteomyelitis and limited use of bispho- procedures.

Table 1. Patient data

Patient numberGender/age Diagnosis Bisphosphonate Site of necrosis Stimulative cause
1 F/72 Multiple myeloma Zoledronate Maxilla (bilateral) Teeth extractions
2 F/69 Breast cancer Pamidronate/ibandronate/ Maxilla and mandibleTeeth extractions and
zoledronate (bilateral) spontaneous procedure
in mandible
3 F/71 Multiple myeloma Pamidronate/zoledronate Maxilla Teeth extractions
4 M/65 Multiple myeloma Pamidronate/zoledronate Mandible Teeth extractions
5 M/63 Prostate cancer Pamidronate/zoledronate Mandible Teeth extractions
6 F/74 Multiple myeloma Zoledronate Mandible Denture trauma
7 M/47 Neuroend-ocrine cancerZoledronate Mandible Spontaneous procedure
8 F/76 Multiple myeloma Pamidronate/zoledronate Mandible Teeth extractions
9 M/65 Prostate cancer Zoledronate Mandible Spontaneous procedure
10 M/72 Lung cancer Zoledronate Mandible Teeth extractions
11 F/59 Fibrous dysplasia Zoledronate Maxilla Spontaneous procedure
590 Dimitrakopoulos et al.

Table 2. Bisphosphonates and exact duration of administration

Patient number Zoledronate Pamidronate " Zoledronate Pamidronate " Ibandronate " Zoledronate
1 30 months
2 6 months " 16 months " 7 months
3 3 years " 2 years
4 3 years " 2 years
5 13 months " 2 years
6 22 months
7 9 months
8 2 years " 1 year
9 18 months
10 18 months
11 6 months

Table 3. Results of the proposed therapeutic protocol

Patient Cessation bisphosphonate Surgical Follow-up
number therapy (months) procedure (months) Complications
1 No cessation Sequestrectomy 2 Recurrence
2 8 Sequestrectomy 4 Complete wound healing
3 3 Debridement 4 Satisfactory wound healing
4 3 Debridement 2 Recurrence
5 4 No 8 Stabilized necrosis
6 3 Debridement 4 Satisfactory wound healing
7 4 No 8 Stabilized necrosis
8 2 Debridement 2 Recurrence
9 3 Sequestrectomy 3 Recurrence
10 4 Debridement 6 Satisfactory wound healing
11 6 Debridement 6 Satisfactory wound healing

None of the patients had previously nates and the surgical procedure varied, necrosis at 3 quadrants (unilaterally at the
received radiation therapy to the head and ranged from 2 to 8 months. In 1 patient maxilla and bilaterally at the mandible)
and neck region but almost all received sequestrectomy was administered with no (Figs. 2 and 3). From the cohort of 11
chemotherapy in accordance with their previous cessation of bisphosphonate ther- patients, 6 revealed bone exposure and
specific type of tumour. The only thing apy (Table 3). necrosis after teeth extractions, in 3 of them
in common was the bisphosphonate ther- it was a spontaneous procedure, while in
apy that was administered to all patients patient 2 the maxillary necrosis was a result
Results
in the treatment of the metastatic or of teeth extractions and the mandibular
not metastatic osteolytic bone lesions. Four patients (36%) presented with max- necrosis was a spontaneous procedure
The bisphosphonates used were mainly illary bone involvement (2 unilateral and 1 and in patient 6 a chronic denture trauma
pamidronate and zoledronate IV (intrave- bilateral) (Fig. 1), 6 (55%) had mandibular was the cause of necrosis. The radiographic
nously) or both in sequence (first pami- bone necrosis and 1 (9%) presented with evaluation revealed regions of necrotic
dronate and then zoledronate). In one case
ibandronate was administered, but it
was followed by zoledronate (Table 1).
The duration of bisphosphonate therapy
was 660 months and was administered
in 1 month or 40-day dosages (Table 2).
No HBO (hyperbaric oxygen) was
received and multiple biopsies and cul-
tures from the sites of the lesions were
performed. The mean follow-up period
was 5 months (28 months).
The treatment protocol followed for
most of the patients in this department
included cessation of bisphosphonate ther-
apy (if possible) and debridement or
sequestrectomy with antibiotic adminis-
tration, including clindamycin for the first
2 weeks, amoxycillin and clavulanic acid
for another 2 weeks and penicillin G for a
period of time which depended on the
microbiology culture of the defect. The
time between cessation of bisphospho- Fig. 1. Bilateral maxillary osteonecrosis in patient 1.
 Bisphosphonate-induced avascular osteonecrosis of the jaws 591

bone which were rather extensive in the

cases of maxillary involvement.
All the biopsy specimens taken from the
area of necrotic bone, including both soft
and hard tissues, were negative for malig-
nancy. Culture results revealed Actino-
myces israeli and Escherichia coli in
patient 2, A. israeli in patient 6, Bacter-
oides melaninogenicous in patient 7 and
normal oral flora in the other patients. All
patients, except for patient 11 with fibrous
dysplasia, were administered several che-
motherapeutic agents with various dura-
tion, according to their oncological
history.
The management of osteonecrosis of
the jaws included surgical debridement
and/or sequestrectomy after cessation of
the bisphosphonate therapy for several
months (from 2 to 8). Patient 1 was not
Fig. 2. Preoperative clinical view of maxillary osteonecrosis in patient 2.
removed from bisphosphonate treatment
and patients 5 and 7 were not willing to
have any surgical procedure after cessa-
tion of bisphosphonate therapy.
The striking result was a complete
wound healing (covered by intact mucosa)
for patient 2 after 8 months cessation
(Fig. 4) and satisfactory healing (bone
exposure less than 12 mm) for patients
3, 6, 10 and 11 after 36 months cessation
of bisphosphonate treatment. Patient 1,
who continued bisphosphonate therapy
during and after sequestrectomy, devel-
oped new regions of necrotic bone which
resulted in complete maxillary destruc-
tion, while in patients 4, 8 and 9 with 2
and 3 months cessation from bisphospho-
nate therapy, the necrosis recurred.
Finally, in patients 5 and 7 who received
no other therapy apart from removal from
Fig. 3. Preoperative orthopantomographic image of maxillary and bilateral mandibular osteo- bisphosphonate treatment, no further
necrosis in patient 2. necrotic bone developed (Table 3).

Discussion
The high incidence of osteonecrosis
especially maxillary in patients who
are receiving bisphosphonates and have
not previously received radiation therapy
in the head and neck region, is in contrast
to current knowledge. MARX et al. first
reported osteonecrotic lesions of the jaws
similar to those of osteoradionecrosis,
which he called drug-induced avascular
osteonecrosis, implying that the destruc-
tion of the vascular complexity of the jaws
mediated by the use of bisphosphonates is
responsible for the necrosis and secondary
infection of the bone matrix13,15.
All the patients referred to this depart-
ment had previously received zoledronate
or pamidronate followed by zoledronate
for the treatment of metastatic bone dis-
Fig. 4. Postoperative complete wound healing after treatment in patient 2. ease and fibrous dysplasia. Both of these
592 Dimitrakopoulos et al.

bisphosphonates, and ibandronate which oxygen administration. In a review of 63 caemia may be a problem and in such
was used in 1 patient prior to zoledronate, cases of osteonecrosis of the jaws asso- cases cessation must be reconsidered
belong to the N-BPs, those that contain a ciated with the use of bisphosphonates, because it is a serious complication that
nitrogen atom located in the R2-side chain. hyperbaric oxygen therapy administered requires immediate regulation due to its
The exact mechanism and the pathways in 2 patients before undergoing surgical life threatening character. In cases of
that lead to the osteonecrotic process treatment had no significant positive impact advanced disease where bisphosphonates
remain unclear. A thorough understanding on the necrotic process. In addition, in the may be part of a palliative therapy for the
of the action of N-BPs and the way that same study, the cessation of bisphospho- patient, jaw osteonecrosis may be of minor
this action differs from the non-N-BPs, in nate therapy alone did not reveal any importance. Recent research shows that
correlation with the macromicroenviron- improvement of the bone necrosis20. Sev- bisphosphonates can be used for preven-
ment of the oral and maxillofacial regions, eral other recommendations for the treat- tion of bone metastasis and retardation of
may give rise to hypotheses for the patho- ment of this entity have been made, disease development by inducing the
genesis of this process. suggesting conservative treatment (mini- apoptosis of malignant cells25. Hence,
At a molecular level the non-N-BPs can mally invasive procedures, administration the disease status of the patient from the
be incorporated metabolically into non- of antibiotics along with 0.12% clorohex- oncologists point of view is crucial to the
hydrolysable analogues of ATP. It is likely idine antiseptic mouthwash)14,23, or more decision to stop bisphosphonate therapy in
that accumulation of these metabolites aggressive procedures (debridement of order to treat jaw osteonecrosis.
inhibits osteoclast function and causes bone sequestra, subtotal or even total resec- Numerous critical questions remain
osteoclast apoptosis. On the other hand, tion of the affected bone followed by pro- unanswered. For example, is there any
the N-BPs are not metabolized, but act as longed antibiotic therapy)1,7,11. interaction between bisphosphonates and
transition state analogues of isoprenoid Surprisingly, it was observed in one of chemotherapy in the development of
lipids inhibiting enzymes of the mevalo- the patients in this study, with an expan- osteonecrosis? How does cell apoptosis
nate pathway5. Most of the isoprenylated sive maxillary necrosis who had already interact with the oral flora environment
proteins identified are small GTPases ceased the bisphosphonates administra- to affect bone matrix degeneration? In this
which are important for osteoclast func- tion for almost 8 months, sequestrectomy study it was assumed that the bisphospho-
tion, including morphology, membrane with viable bleeding bone surgical mar- nate-induced apoptosis of osteoclasts and
raffling and apoptosis2,3. gins had excellent wound healing out- keratinocytes in combination with the oral
The most potent N-BPs (pamidronate come. From 6 months after surgery, no and sinus flora creates a destructive micro-
and especially zoledronate) are great inhi- further exposed bone was seen. Conver- environment that causes osteonecrosis,
bitors of protein isoprenylation in osteo- sely, in 1 patient with a bilateral maxillary while a significant decrease in circulating
clasts, which explains why their anti- osteonecrosis, sequestrectomy without levels of VEGF mediated by bisphospho-
resorptive effects are at least 10,000 times cessation of bisphosphonate administra- nates leads to the apparent ischemic
more powerful than the non-N-BPs19. tion had a worse outcome, with the necro- charges in the bone matrix of the jaws.
This molecular pathway of action leads, tic bone expanding. In 4 other patients Further research, however, is necessary to
at a cellular level, to induction of osteo- whose bisphosphonate administration prove and clarify all the biochemical,
clast apoptosis which might be the most had been ceased for 36 months, the molecular and cellular interactions that
important mechanism of anti-resorptive wound-healing outcome was satisfactory. point to these hypotheses.
effect9. Finally, inhibition of bone resorp- Cessation of bisphosphonate treatment for The efficacy of bisphosphonates for the
tion by osteoclast apoptosis and reduced 2 and 3 months did not have a satisfactory treatment of osteoporosis, hypercalcaemia
bone remodeling compromises normal impact on the necrotic bone lesions for of malignancy, Pagets disease, bone pain
bone homeostasis. another 3 patients. Surgical debridement and bone metastasis has been extensively
The bisphosphonate-induced compro- has not been administered in the 2 remain- documented through the last 3 decades.
mise in vascularity of the bone matrix ing patients, but the cessation of bispho- Osteonecrosis of the jaws after pamidro-
of the jaws through underexpression of sphonate therapy for 4 months now, seems nate or zoledronate administration for at
vascular endothelial growth factor to have limited the progression of the least 6 months is a serious side effect with
(VEGF)10,21,24 and endothelial cells process. quite challenging management. Attention
apoptosis12,16,17 may give enough evi- We believe that discontinuity of bispho- must be paid to prescribing those agents,
dence for the explanation of the jaw osteo- sphonate therapy, if possible, combined while research is needed to unravel both
necrosis. The increased apoptotic rate of with surgical debridement to obtain clear the exact pathogenesis and the treatment
both osteoclasts and keratinocytes18 on the and bleeding margins together with long- of choice for this complication.
one hand, which reduce and destruct the term antibiotic therapy administration, is
immune keratinocyte barrier of the oral the treatment of choice for osteonecrotic
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