Int. J. Oral Maxillofac. Surg.

2010; 39: 10971102

doi:10.1016/j.ijom.2010.04.054, available online at http://www.sciencedirect.com

Clinical Paper
Oral Medicine

Clinical comparison of patients M. Kos, D. Brusco, J. Kuebler,

W. Engelke
Department of Maxillofacial Surgery, Klinikum

with osteonecrosis of the jaws, Minden, Hans-Nolte-Strasse 1, 32-429

Minden, Germany

with and without a history of

bisphosphonates administration
M. Kos, D. Brusco, J. Kuebler, W. Engelke: Clinical comparison of patients with
osteonecrosis of the jaws, with and without a history of bisphosphonates
administration. Int. J. Oral Maxillofac. Surg. 2010; 39: 10971102. # 2010
International Association of Oral and Maxillofacial Surgeons. Published by Elsevier
Ltd. All rights reserved.

Abstract. This retrospective study aimed to evaluate the role of bisphosphonates in

jaw osteomyelitis. 29 patients were included: 18 had been treated with
bisphosphonates (12 with multiple myelomas, 3 with breast carcinomas, 2 with
prostate carcinomas, and 1 with osteoporosis). Of 11 control patients, 2 had breast
carcinomas, 2 had bronchial carcinomas, and 7 had no cancer. Descriptive and
statistical evaluations were conducted to investigate the influence of chemotherapy,
corticosteroids, stem cell transplantation, and bisphosphonates on the development
and clinical picture of osteomyelitis. Both groups had similar disease histories,
clinical pictures, treatment methods, and outcome. Wound dehiscence frequencies
were also similar (MannWhitney rank sum test 1.66  1.5 vs. 1.45  2.0
p = 0.393). Chemotherapy, steroid therapy, stem cell transplantation, or
bisphosphonate administration did not correlate with the clinical picture. Neither
the duration of therapy nor the type of bisphosphonate influenced the clinical picture
(negative Fishers tests). The bisphosphonate group showed a characteristic
settlement of Actinomyces in the exposed bone (positive Fishers test, p = 0.021).
These results suggested that osteomyelitis developed as a consequence of the Keywords: Osteonecrosis; Osteomyelitis;
simultaneous, cumulative action of many factors. Bisphosphonates played a role Bisphosphonates; Jaws.
comparable to other predisposing features. Coating the jaws with bisphosphonates
could promote the settlement of Actinomyces. Accepted for publication 21 April 2010

Owing to their unique ability to inhibit bone
resorption, bisphosphonates (BPs) have
been used for several years for treating
osteoporosis, Pagets disease, and fibrous
dysplasia.5 Recently, they have become
part of chemotherapeutic protocols for
managing bone invading tumours. The ben-
eficial effects of BPs include significant
reductions in pain, pathological fractures,
osteolytic lesion size, and the need for
subsequent bone surgery.13,22,24 A growing
number of studies have recognized the
crucial role of BPs in provoking heavy,
chronic, therapy-resistant osteonecrosis of
the jaws (ONJ). BPs are thought to influ-
ence ONJ by reducing bone metabolism,
reducing osteoclast recruitment, inducing
osteoclast-inhibiting factor production, and
impairing angiogenesis.13,14,24
Jaws are particularly subject to infection,
due to their contact with the external envir-
onment, their susceptibility to trauma, their
rich saprophytic flora, and the presence of
teeth. The jaws are protected by a high rate

0901-5027/1101097 + 06 $36.00/0 # 2010 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
1098 Kos et al.
of oral epithelium regeneration and a sub-
stantial blood supply. Serious bony com-
plications are seldom triggered by
potentially infectious conditions, such as
open fractures, neglected teeth, periodontal
abscesses, ill-fitting dentures, injuries to the
mucosa, and facial wounds. The develop-
ment of osteomyelitis and ONJ requires
conditions that alter the healthy processes
of immunity, blood supply, or cellular
activity, and destroy natural defences. For
example, diabetes mellitus, metabolic bone
disorders, anti-cancer therapy, or neoplas-
matic infiltration can contribute to the
development of ONJ.13 Diabetes mellitus
is associated with microvascular ischae-
mia, endothelial cell dysfunction, osteocyte
apoptosis, and reduced bone turnover.11
Anti-cancer therapy, combined with
cytostatics, corticosteroids, and stem cell
transplantation, leads to general immuno-
suppression, bone marrow degeneration,
vasculitis, reduced blood flow, and osteo-
penia.7,11,15,19,2123 Multiple myelomas
that develop in bone marrow and cancers
that metastasise to the skeletal system
(breast, prostate, kidney, lung) weaken
bone structure by increasing osteoclast
numbers and enhancing their resorptive
activity.9 For example, in patients with
multiple myelomas, ANDERSEN et al.
demonstrated that osteolytic lesions con-
tained 30% of malignant, hyperactive,
polynuclear osteoclasts that originated
from hybrid fusions between myeloma
cells and normal osteoclasts.3
Until recently, BPs were considered
safe drugs with only a few side effects.
BPs are pyrophosphate analogues, in
which the oxygen atom in the basic chain
(POP) is substituted with carbon (PC
P). BPs possess a high affinity for hydro-
xyapatite and are resistant to hydrolysis by
bone phosphatases. This contributes to
extended bone deposition, over several
years.24 The mechanism of action under-
lying the antiresorptive potential of a BP is
determined by whether it has a nitrogen
molecule in the side chain. Non-nitrogen
BPs (etidronate, clodronate, tiludronate)
are phagocytosed by osteoclasts and meta-
bolised to non-hydrolysable cytotoxic
ATP analogues; this handicaps the mito-
chondrial function of the cell and results in
apoptosis.24 In contrast, the more potent,
nitrogen-containing BPs (aledronate,
pamidronate, zoledronate, risedronate)
can inhibit osteoclasts by interrupting
the mevalonate pathway of cholesterol
synthesis.
BPs were shown to exert a protective
effect on bone tissue in avascular necrosis
of the long bones and chronic sclerosing
osteomyelitis of the jaws.1,16 Zoledronate
had a beneficial influence on new bone Results
formation during distraction osteogen-
The clinical characteristics of the patients
esis.12,17 Several reports describe ONJ in
treated with BPs and controls are given in
patients who were treated for a long time
Tables 1 and 2, respectively. Surgical
with BPs due to bone metabolic disorders
procedures usually preceded the onset of
such as Pagets disease or fibrous dyspla-
symptoms. These affected 12/18 (67%) of
sia.5,24
the patients treated with BPs and 9/11
These data raised the question of
(73%) of the control subjects, and
whether BPs might play a role in ONJ.
included, respectively, teeth extractions
To address this question, the authors
(8/18; 6/11), cystectomies (2/18; 1/11),
undertook a retrospective analysis of a
implant insertions (2/18; 1/11), or dentoal-
group of patients who had been treated
veolar trauma (0/18; 1/11) The most com-
with BPs for maxillary and mandibular
mon clinical findings were swelling and
osteomyelitis that did not have a directly
pain that accompanied a mucosa injury
associated pathological condition.
and an area of exposed and devitalised
bone. Areas of bone necrosis were situated
Materials and methods predominantly in the postero-lateral part
of the mandible (BP-treated: 13/18 and
The authors retrospectively reviewed the
controls: 10/11; not significantly differ-
records of patients treated for ONJ from 1
ent). In all patients, a bone biopsy ruled
January 2003 to 31 December 2006. The
out malignancy at the site of infection. In
records included anamnesis, local status at
two patients with multiple myelomas
admission and during treatment, surgery
showing an extremely high wound dehis-
reports, and accessible panoramic X-rays.
cence rate, malignant plasmatic cells were
The authors evaluated bone infections of
found 1 year after primary surgery. Sur-
uncertain aetiology with delayed wound
gical treatment was provided to 25/29
healing, bone sequestration, abscess for-
patients (16/18; 9/11). The method of
mation, and recurrent wound dehiscence;
treatment was independent of receiving
clear cases of osteoradionecrosis or open
BP administration.
fractures were excluded.
The recurrence rate of wound dehis-
The 29 patients included in this study
cence in patients who received BP
had a mean age of 62  13 years and a
(1.67  1.5) was not significantly
male to female ratio of 14:15. The patients
different from that in patients who did
were divided into two groups. The first
not receive BP therapy (1.45  2.0,
consisted of 18 patients that had received
p = 0.393). There were no detectable
BPs, including 12 with multiple myeloma,
effects of chemotherapy, steroid therapy,
3 with breast carcinoma, 2 with prostate
or stem cell transplantation on the dete-
carcinoma, and 1 with osteoporosis. The
rioration of wound healing (negative Fish-
second group (controls) consisted of 11
ers exact tests p = 0.484, p = 0.104, and
patients with no history of bisphosphonate
p = 0.142, respectively). There were no
administration, but with similar anamnesis
associations between the wound dehis-
and clinical symptoms, including 2 with
cence rate and the duration of BP therapy
breast carcinoma, 2 with bronchial carci-
or the kind of drug (negative Fishers
noma, and 7 without cancer. The presence
exact tests; p = 0.273 and p = 0.576,
of tumour metastases in the affected areas
respectively). A high incidence of Actino-
was ruled out by bone biopsy.
myces settlement was observed in exposed
A descriptive method was used for com-
areas of the bone significantly more often
parisons between groups of the location of
in the BP group (11/18; 61%) compared
the infection, clinical picture, treatment
with the controls (2/11; 18%) (positive
method, pattern of wound healing, and
Fishers exact test, p = 0.021) (Table 3).
co-morbidity. A MannWhitney rank
sum test was used to evaluate differences
in the mean number of wound dehiscences
Discussion
between study groups. Fishers exact test
was used to evaluate the relationship Controversy over the role of BPs in ONJ
between the following independent cate- inspired the authors to investigate this
gorical variables: chemotherapy, corticos- topic. They studied a group of patients
teroids, stem cell transplantation, BP who had been treated with BPs and had
administration, time of BP administration, subsequently developed inflammatory
type of drug (pamidronate vs. zoledro- symptoms in the maxilla or mandible.
nate), number of wound dehiscences, The control patients had been treated for
and Actinomyces colonisation. ONJ in the authors department at the
Statistical significance was defined as same time, and although they presented
p < 0.05. a similar history, they had not been treated
Table 1. Characteristics of patients treated with bisphosphonates.
Diagnosis Stem cell Time ofb Location of
Sex Agea Cytostatics Steroids transpl. Bisphosphonate administr. osteomyelitis Therapy Recurrencesc Actionomycosis
Cancer Additional
1 , 65 BCd + Zometae 35 Maxilla left Bone shaving 2
2 , 64 BC + Zometa 12 Mandible corps left Bone shaving 1 +
3 , 78 BC + + Pamidronatef 34 Mandible corps left Bone shaving 3 +
4 , 70 Bronchial + Fosamaxg 60 Mandible corps bil. Decortication 2 +
asthma,
Anaemia
5 < 70 PCh Liver + Zometa 12 Mandible corps right Incision 1
metastases
6 < 67 PC + Zometa 24 Mandible corps right Teeth extr. 0
7 < 69 MMi Venous + + + Zometa 23 Maxilla bilateral Bone shaving 2 +
insufficiency
8 < 71 MM + Zometa 33 Mandible corps left Bone shaving 2 Candida
9 , 58 MM Atopic asthma, + + + Pamidronate 16 Mandible corps left Bone shaving 2
Diabetes
10 , 75 MM Hypertension + + Pamidronate 26 Mandible corps bil. Bone shaving 1 +
11 < 65 MM Anaemia, + + + Pamidronate 18 Maxilla right Bone shaving 0 +
generalised
Herpes
12 , 78 MM Diabetes, + + + Pamidronate 15 Maxilla right Bone shaving 4 +
Hypertension
13 , 63 MM Renal + + + Pamidronate 84 Mandible bil. Bone shaving 6 +
insufficiency,
Coxarthrosis
bil.
14 , 58 MM + + Zometa 48 Mandible corps left Incision 0 +
15 < 46 MM + + + Zometa 46 Mandible corps right Bone shaving 1
16 , 75 MM Renal + + + Pamidronate 58 Mandible corps bil Bone shaving 1

Bisphosphonates in jaw osteomyelitis

insufficiency
17 < 53 MM + + + Pamidronate 48 Mandible corps left, Decortication 2 +
maxilla
18 , 77 MM + + Zometa 36 Maxilla right, Bone shaving 0 +
mandible front
67  8.9j 34.9  19.5 1.66  1.5
a
Years.
b
Months.
c
At the time of the diagnosis number.
d
Breast carcinoma.
e
Doses, 4 mg every 4 weeks i.v.
f
Doses, 6090 mg every 3 weeks i.v.
g
Doses, 70 mg per week p.o.
h
Prostate carcinoma.
i
Multiple myelomas.
j
Mean  standard deviation.

1099
1100 Kos et al.

Table 2. Characteristics of patients not treated with bisphosphonates.

Diagnosis Location of
Nr Sex Agea Cytostatics Steroids osteomyelitis Therapy Recurrencesb Actionomycosis
Cancer Additional
1 , 66 BCc Pleurocarcinosis + Mandible bilateral Decortication 0 +
2 , 48 BC + + Mandible corps front Bone shaving 1
3 < 66 BrCd + Mandible corps front Decortication 1
4 < 56 BrC + Mandible corps right Decortication 0
5 < 56 Mandible corps right Bone shaving 1
6 , 66 Coronary Mandible corps left Decortication 7
insufficiency
7 < 54 Heart infarct, Mandible corps right Decortication 1
Artificial heart
valve
8 < 69 Maxilla right Decortication 2
9 , 61 Mandible corps left Bone shaving 3
10 < 48 Mandible corps right Antibiotics 0
11 < 45 Alkoholism, Mandible corps right Incision 0 +
Cachexia
62  13e 1.45  2.0
a
Years.
b
Number.
c
Breast carcinoma.
d
Bronchial carcinoma.
e
Mean  standard deviation.

Table 3. Rates and proportions of independent categorical variables compared between BP-
treated and control groups computed with Fishers exact test.
Variable 1 Variable 2 Significance
Chemotherapy Deterioration of wound healing Not significant p = 0.484
Steroid therapy Deterioration of wound healing Not significant p = 0.104
Stem cell transplantation Deterioration of wound healing Not significant p = 0.142
Duration of BP therapy Deterioration of wound healing Not significant p = 0.273
Type of bisphosphonate Deterioration of wound healing Not significant p = 0.576
(zoledronate vs.
pamidronate)
Settlement of Actinomyces BP vs. non-BP group Significant p = 0.021
with BPs. The authors aimed to identify the skeletal system in a particular manner.
differences, peculiarities, or characteris- Multiple myelomas can form hybrids by
tics of the ONJ associated with BP treat- the fusion of normal osteoclasts with
ment compared with ONJ that developed tumour cells; these hybrids possess an
independent of BP treatment. enormous capacity for osteolysis.3 Bony
The results indicated that, compared destruction derived from malignancy was
with the control group, patients treated detected in some cases after a standard
with BP did not show a noticeable wor- histopathological examination had ruled
sening of the course or prognosis of ONJ. out jaw invasion. In two patients with
The groups were similar in the onset of multiple myelomas that presented an
symptoms, time of incubation, intensity of extremely high recurrence rate, malignant
pain, and pattern of wound healing. There plasmatic cells were found at the site of
was no significant difference between the persistent osteomyelitis 1 year after the
groups in the recurrence of wound dehis- initial negative histology. Breast, lung, or
cences; this was described in many reports prostate carcinoma can produce cytokines
as a hallmark of bisphosphonate asso- that highly activate the resorptive activity
ciated osteonecrosis.4,6,13,14 It is not clear of osteoclasts. Humorally mediated bone
whether BPs could be solely responsible degeneration can be related to the secre-
for the development of osteomyelitis in tion of parathyroid hormone-related pep-
patients who are simultaneously under the tide, receptor activator of NF-kappa B
influence of other potentially osteonecro- ligand, macrophage inflammatory peptide
tic or inflammatory co-morbidities. The 1-a, interleukin-3, or interleukin-7.9 Sev-
present patients predominantly had multi- eral studies showed that breast tumour cell
ple myelomas and breast carcinoma (83% lines could cause direct, non-osteoclast-
in the BP group). These tumours can affect mediated bone resorption.25 Cancer
patients must typically undergo extremely
arduous treatments that comprise different
combinations of cytostatics, corticoster-
oids, and stem cell transplantation. Each
of these treatments possesses the potential
for inducing osteonecrosis. Chemotherapy
inhibits humoral and cellular immune
responses and produces osteopenia; this
predisposes patients to infection. Accord-
ing to TARASSOFF and CSERMAK, the inci-
dence of ONJ in patients with cancer is
fourfold higher than that in the healthy
population.22 SCHWARZ described ONJ as a
consequence of cancer chemotherapy in
patients with haematological malignant
disease.19 Similar data were presented
by SUNG et al.21 Steroid therapy has been
associated with several negative effects in
bone tissue. For example, corticosteroids
have been associated with osteopenia,
fatty emboli in small bone marrow vessels,
and reduced sinusoidal blood flow, in
addition to their immunosuppressive
actions; these conditions contribute to an
increased risk of inflammatory events.15
TAUCHMANOVA et al. and GAHNDI et al.
showed that stem cell transplantation
was associated with the development of
either avascular osteonecrosis or bone
dystrophy.7,23
In the present study, there was no cor-
relation between the pattern of wound
healing and a diagnosis of cancer, che-
motherapy, steroid therapy, or stem cell
transplantation. Any one of these factors
could influence the development of ONJ,
but together, they could also contribute to
bone dystrophy. In the BP group, 17/18

(94%) patients had carcinomas. In the
control group, only 4/11 (36%) had carci-
nomas. Osteoporosis was present in 12/29
(41%) cases. In all, 23/29 (88%) patients
had a condition that could contribute to the
development of ONJ on the basis of bone
weakness due to cancer, anti-cancer ther-
apy, or substantial osteoporosis. SATO-
MURA et al. and Albuquerque et al.
showed that BPs could also produce bone
dystrophic changes that might lead to a
refractory osteomyelitis with little
response to treatment.2,18 It is likely that,
in this study, the aetiology of ONJ was
multifactorial, and the role of BPs was
comparable to that of the other factors.
The present study did not include a suffi-
cient number of treated patients or rele-
vant data to draw final conclusions about
whether factors such as chemotherapy,
steroid therapy, stem cell transplantation,
or BP therapy had any influence on the
aetiology or incidence of ONJ.13,14,24
It is difficult to ascribe a predominate
role in evoking ONJ to BPs, because in
patients treated with intravenous adminis-
tration of zoledronate or pamidronate (the
two BPs most suspected of evoking ONJ)
the incidence varied from 0.7% to 10%.24
The patients without cancer who were
given BPs to treat Pagets disease or
fibrous dysplasia rarely showed signs of
ONJ. This is supported by the results of
CHAPURLAT et al. (58 cases) and by the
authors observations (50 cases; unpub-
lished results) in patients with fibrous
dysplasia that had been treated surgically
and then given pamidronate and followed
up for over 5 years.5 The most recent
studies on distraction osteogenesis showed
that zoledronic acid exerted a positive
effect on new bone formation. In studies
by LITTLE et al. and PAMPU et al., bone
mineral density and bone mineral content
of regenerated tissue were 3050% greater
in the groups treated with zoledronate
compared with the control groups.12,17
Numerous studies have described the ben-
eficial effects of BPs in the treatment of
avascular necrosis of the long bones, scler-
osing osteomyelitis of the jaws, and cancer
cell adhesions in bone matrix.1,2,13,16,18,24
It is debatable whether a substance with
such a favourable influence on bone pre-
servation could simultaneously be respon-
sible for the complete opposite effect. In
order to reconcile these opposing effects,
it was postulated that the duration of the
therapy and cumulative dose of BPs might
be crucial to the development of ONJ.4,6
The present study does not support this
hypothesis. The authors did not find a cor-
relation between the duration of the ther-
apy, the type of BP, the severity of ONJ, or
Bisphosphonates in jaw osteomyelitis
treatment outcome. In particular, they
found that zoledronate therapy was not
more destructive than pamidronate therapy.
These results were opposite to those
reported by DIMOPOULOS et al. and BAMIAS
et al. In those studies, a strong association
was found between the administration of
amino-BPs and ONJ, particularly with
zoledronate therapy.4,6 These discrepan-
cies require further evaluation. The present
results appear to be more consistent with
studies in ovariectomised rats treated with
high doses of zoledronic acid for over 1
year that showed increased bone density
and mechanical strength with no signs of
frozen bone or osteomalacia.10
In patient examinations, the authors
found that a striking number of patients
treated with BPs were infected with Acti-
nomyces colonies, in contrast to the con-
trol group, in which this infection
appeared only rarely. Previous reports
have confirmed this finding.13,24 Numer-
ous studies have shown that Actinomyces
is a common saprophytic pathogen in the
oral cavity in conditions of immunosup-
pression or cachexia. The presence of
Actinomyces in the patients may have
resulted from the toll taken by the disease
and the arduous oncological treatment.
The authors found a strong correlation
between the administration of BPs and
the appearance of Actinomyces. Although
a correlation does not prove a causative
relationship, it suggests that BP deposition
in a bone might promote the settlement of
Actinomyces. Consistent with this obser-
vation, GANGULI et al. reported an
increased adhesion of Staphylococcus
aureus to hydroxyapatite joint prostheses
coated with clodronate or pamidronate.8
The primary limitation of this study was
the limited number of patients, which did
not allow definitive conclusions to be
drawn. It is difficult to define the role of
BPs in the course of ONJ in the midst of
conflicting data and controversy. Cur-
rently, most of the data is from uncon-
trolled studies on collections of patients. A
series of controlled studies are required to
determine more definitively the role of
BPs in ONJ.13,14,20,24
The present results suggest that BPs do
not play a predominant role in the course
of ONJ. In this study, the course of ONJ
was modulated by the simultaneous,
cumulative action of many factors, and
the role of BPs was probably comparable
to that of other predisposing factors. These
results supported the notion that coating
the jaw bone with BPs could promote the
settlement of Actinomyces, and thus, influ-
ence the course of ONJ, but this hypoth-
esis requires further investigation.
1101
Competing interests
None declared.
Funding
None.
Ethical approval
Not required.
References
1. Agarwala S, Jain D, Joshi VR, Sule A.
Efficacy of alendronate, a bisphospho-
nate, in the treatment of AVN of the
hip. A prospective open-label study.
Rheumatology 2005: 44: 352359 Erra-
tum in: Rheumatology 2005; 44: 569.
2. Albuquerque MA, Melo ES, Jorge
WA, Cavalcanti MG. Osteomyelitis
of the mandible associated with autoso-
mal dominant osteopetrosis: a case report.
Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 2006: 102: 9498.
3. Andersen T, Boissy P, Sondergaard
T, Kupisiewicz K, Plesner T, Rasmus-
sen T, Haaber J, Kolvraa S, Delaisse
JM. Osteoclast nuclei of myeloma
patients show chromosome translocations
specific for the myeloma cell clone: a new
type of cancer-host partnership? J Pathol
2007: 211: 1017.
4. Bamias A, Kastritis E, Bamia C, Mou-
lopoulos LA, Melakopoulos I, Bozas
G, Koutsoukou V, Gika D, Anagnos-
topoulos A, Papadimitriou C, Terpos
E, Dimopoulos M. Osteonecrosis of the
jaw in cancer after treatment with bispho-
sphonates: incidence and risk factors. J
Clin Oncol 2005: 23: 85808587.
5. Chapurlat RD, Hugueny P, Delmas
PD, Meunier PJ. Treatment of fibrous
dysplasia of bone with intravenous pami-
dronate: long-term effectiveness and eva-
luation of predictors of response to
treatment. Bone 2004: 35: 235242.
6. Dimopoulos MA, Kastritis E, Ana-
gnostopoulos A, Melakopoulos I,
Gika D, Moulopoulos LA, Bamia C,
Terpos E, Tsionos K, Bamias A. Osteo-
necrosis of the jaw in patients with multi-
ple myeloma treated with
bisphosphonates: evidence of increased
risk after treatment with zoledronic acid.
Haematologica 2006: 91: 968971.
7. Gandhi MK, Lekamwasam S, Inman I,
Kaptoge S, Sizer L, Love S, Bear-
croft P, Milligan TP, Price CP, Mar-
cus RE, Compston JE. Significant and
persistent loss of bone mineral density in
the femoral neck after haematopoietic
stem cell transplantation: long-term fol-
low-up of a prospective study. Br J Hae-
matol 2003: 121: 462468.
8. Ganguli A, Steward C, Butler SL,
Philips GJ, Meikle ST, Lloyd AW,
Grant MH. Bacterial adhesion to
1102 Kos et al.
bisphosphonate coated hydroxyapatite. J
Mater Sci Mater Med 2005: 16: 283287.
9. Guise TA. Molecular mechanisms of
osteolytic bone metastases. Cancer
2000: 15(12 Suppl.):28922898.
10. Hornby SB, Evans GP, Hornby SL,
Pataki A, Glatt M, Green JR. Long-
term zoledronic acid treatment increases
bone structure and mechanical strength of
long bones of ovariectomized adult rats.
Calcif Tissue Int 2003: 72: 519527.
11. Khamaisi M, Regev E, Yarom N, Avni
B, Leitersdorf E, Raz I, Elad S. Pos-
sible association between diabetes and
bisphosphonate-related jaw osteonecro-
sis. J Clin Endocrinol Metab 2007: 92:
11721175.
12. Little DG, Smith NC, Williams PR,
Briody JN, Bilston LE, Smith EJ, Gar-
diner EM, Cowell CT. Zoledronic acid
prevents osteopenia and increases bone
strength in a rabbit model of distraction
osteogenesis. J Bone Miner Res 2003: 18:
13001307.
13. Marx RE, Sawatari Y, Fortin M,
Broumand V. Bisphosphonate-induced
exposed bone (osteonecrosis/osteopetro-
sis) of the jaws: risk factors, recognition,
prevention, and treatment. J Oral Max-
illofac Surg 2005: 63: 15671575.
14. Migliorati CA, Schubert MM, Peter-
son DE, Seneda LM. Bisphosphonate-
associated osteonecrosis of mandibular
and maxillary bone: an emerging oral
complication of supportive cancer ther-
apy. Cancer 2005: 104: 8393.
15. Mirzai R, Chang C, Greenspan A,
Gershwin ME. The pathogenesis of
osteonecrosis and the relationships to cor-
ticosteroids. J Asthma 1999: 36: 7795.
16. Montonen M, Kalso E, Pylkkaren L,
Lindstrorm BM, Lindqvist C. Diso-
dium clodronate in the treatment of dif-
fuse sclerosing osteomyelitis (DSO) of
the mandible. Int J Oral Maxillofac Surg
2001: 30: 313317.
17. Pampu AA, Dolanmaz D, Tuz HH,
Karabacakoglu A. Experimental eva-
luation of the effects of zoledronic acid on
regenerate bone formation and osteoporo-
sis in mandibular distraction osteogen-
esis. J Oral Maxillofac Surg 2006: 64:
12321236.
18. Satomura K, Kon M, Tokuyama R,
Tomonari M, Takechi M, Yuasa T,
Tatehara S, Nagayama M. Osteopetro-
sis complicated by osteomyelitis of the
mandible: a case report including char-
acterization of the osteopetrotic bone. Int
J Oral Maxillofac Surg 2007: 36: 8693.
19. Schwartz HC. Osteonecrosis of the jaws:
a complication of cancer chemotherapy.
Head Neck Surg 1982: 4: 251253.
20. Schwartz HC. Osteonecrosis: the need
for an evidence-based approach. J Oral
Maxillofac Surg 2006: 64: 1177.
21. Sung EC, Chan SM, Sakurai K,
Chung E. Osteonecrosis of the maxilla
as a complication to chemotherapy: a case
report. Spec Care Dentist 2002: 22: 142
146.
22. Tarassoff P, Csermak K. Avascular
necrosis of the jaws: risk factors in meta-
static cancer patients. J Oral Maxillofac
Surg 2003: 61: 12381239.
23. Tauchmanova L, De Rosa G, Serio B,
Fazioli F, Mainolfi C, Lombardi G,
Colao A, Salvatore M, Rotoli B,
Selleri C. Avascular necrosis in long-
term survivors after allogeneic or auto-
logous stem cell transplantation: a single
center experience and a review. Cancer
2003: 97: 24532461.
24. Woo SB, Hellstein JW, Kalmar JR.
Systematic review: bisphosphonates and
osteonecrosis of the jaws. Ann Intern Med
2006: 144: 753761.
25. Yoneda T, Sasaki A, Mundy GR.
Osteolytic bone metastasis in breast can-
cer. Breast Cancer Res Treat 1994: 32:
7384.
Address:
Marcin Kos
Department of Maxillofacial Surgery
Klinikum Minden
Hans-Nolte-Strasse 1
32-429 Minden
Germany
Tel.: +49 571 790 3701
fax: +49 571 790 3721
E-mail: mkos@poczta.onet.pl