Assistant Professor, University Dentistry Clinic-Alfonso X El Sabio, University of Madrid, SpainSpain
Maxillofacial Surgery, Department of Dentistry and Stomatology, Medical Association of Char- tered Zaragoza, Madrid, SpainSpain
Head of Studies of Dentistry, University Alfonso X El Sabio, Madrid, SpainSpain
Department of Dentistry and Stomatology, Madrid, SpainSpain
Department of Dentistry and Stomatology (Oral Periodoncia Surgery), Madrid, SpainSpain
Departament of Dentistry and Stomatology, Oral Implants Surgery, University Alfonso X el Sabio, Madrid, Spain ABBREVIATIONS: ONJ: Osteonecrosis of the Jaw; AAOMS: American Association of Oral and Maxillofacial Surgeons.
Also available as PDF (figures and tables appear in the PDF).
Bisphosphonates are inhibitors of osteoclastic activity and hence cause inhibition of bone resorption.1-3 These drugs, which are synthetic analogy of natural pyrophosphate, have proven their effectiveness in the treatment of diverse metabolic bone diseases related to quantitative alterations, as is the case of osteoporosis,4-6 or qualitative ones, as in Paget’s disease.7 The most common way for their administration is orally.5 These anti-resorptive drugs cause an increase of bone mineral density and a quick decrease of fracture risk.8-13 They are also effective in oncology patients (breast cancer, prostate cancer, lung cancer, and multiple myeloma, among others).14-19 Additionally, these medicines reduce the symptoms of bone pathology (bone pain, delay of the first new bone event, reduction in fracture appearance).4,17-19 They are normally administered intravenously. Bisphosphonates have anti-cancer effect alone or in combination with other chemotherapy treatments, as they maximize antineoplastic effects.20 In pediatrics, they are used in the treatment of diseases related to abnormal calcinosis or ectopic bone formation, as is the case of osteogenesis imperfect.
Bisphosphonates are inhibitors of osteoclastic activity and hence cause inhibition of 1-3 bone resorption.1-3 These drugs, which are synthetic analogy of natural pyrophosphate, have
proven their effectiveness in the treatment of diverse metabolic bone diseases related to quan- 4-6 7 titative alterations, as is the case of osteoporosis,4-6 or qualitative ones, as in Paget’s disease.7
The most common way for their administration is orally.5 These anti-resorptive drugs cause an 8-13 increase of bone mineral density and a quick decrease of fracture risk.8-13 They are also effective
in oncology patients (breast cancer, prostate cancer, lung cancer, and multiple myeloma, among 14-19 others). Additionally, these medicines reduce the symptoms of bone pathology (bone pain, 4,17-19 delay of the first new bone event, reduction in fracture appearance). They are normally ad-
ministered intravenously. Bisphosphonates have anti-cancer effect alone or in combination with
other chemotherapy treatments, as they maximize antineoplastic effects.20 In pediatrics, they are
used in the treatment of diseases related to abnormal calcinosis or ectopic bone formation, as is 21-23 the case of osteogenesis imperfect.
Based on a total of 36 cases, Marx, et al. reported an adverse effect of the use of these
drugs, which is called Osteonecrosis of the Jaw (ONJ).24 Ruggiero, et al. further reported that of
a total of 63 cases of patients with ONJ, 11.1% suffered originally from osteoporosis.2
Since then, numerous medical entities, scientific associations and expert committees 25-28 16 have researched this adverse effect. It is known that it can appear spontaneously, with an
estimated prevalence of 50% in the case of intravenously administered bisphosphonates and
30% in the case of oral administration. On the other hand, it is usually associated with a trigger 30that invades the integrity of the bone tissue (e.g. tooth extractions, implants, periapical surgery 36 37,38
certain sucsystemic pathologies, presence of dental inflamma- 1,28-35,36, 37-40 tory pathologies, or ageing.
Certain measures and attitudes exist that can decrease
the incidence of this pathology. Referral to a dentist for an oral-
dental check and elimination of focuses that can put the patients
at risk is advised when they are about to receive this therapy,
since this oral and maxillofacial complication decreases the pa-
tients’ quality of life and involves an important health cost, as
well as monetary expenditure for the patient.
A traumatic interventions are important in order to
minimize the incidence of this dreaded effect in patients already
undergoing treatment with bisphosphonates.
Once the injury is set, some experts think that the clini-
cal expressions or symptoms of ONJ can improve by temporarily
or permanently discontinuing the bisphosphonates medication.
They advise conservative or minimally aggressive treatments
combined with long-lasting antibiotic therapy.
It is desirable for specialists involved in administration
of these therapies to count on studies designed with consensual,
globally unified protocols that provide them with useful, vali-
dated information.
In this study, we present a case of ONJ in a patient un-
dergoing oral bisphosphonates treatment.
A sixty-two-year-old woman undergoing oral bisphos-
® phonate (Boniva®) treatment for osteoporosis for over 3 years.
The patient attended a private clinic for right top canine extrac-
tion due to mobility. Six weeks later, she reported pain. Dur-
ing exploration, a gingival fistula with discharge (Figure 1) was
observed, and therefore an intraoral radiography was performed
(Figure 2).
Analgesic (Paracetamol 650 mg) and antibiotic (Amox-
icilin/Clavulanic acid 1000 mg/125 mg, 2 pills every 12 hours)
treatment was established for 15 days, combined with home
mouthwash using chlorhexidine 0.12%. An appointment
41-46
37,46-48
Figure 2. Radiologic image of the number 13 post-extraction socket. Osteolytic lesion can be observed. 45,49-51 After 8 weeks of persistent symptoms, a case of post- extraction ONJ was confirmed, American Association of Oral 15,28,54-56
and Maxillofacial Surgeons (AAOMS) 2006. The same
conservative treatment was maintained for 15 more days, her
prescription doctor was advised to withdraw the bisphosphonate
medication and another appointment was made for a new control
check.37 Finally, it was decided to remove the falling necrotic tis- 1,53 sue by surgical sequestrectomy, performed with the use of lo-
cal anaesthesia. The underlying bone was not operated on except
for a slight curettage (Figure 3).
It was a case of ONJ at clinical stage II, according
the American Association of Oral and Maxillofacial Surgeons
37,52-53 2,57 (AAOMS) classification. The case evolved favourably, and
with complete resolution.
Patients attending dental consultations with previous
records of undergoing or having undergone oral bisphospho-
nates treatment (for postmenopausal, glucocorticoid, or male
osteoporosis) are becoming more frequent.
The incidence of ONJ derived from oral bisphospho-
nates is lower than in the case of intravenous administering. Ad-
ditionally, existing literature describes the extent and severity of
these injuries to be less significant in the case of orally adminis-
tered bisphosphonates, having a more favourable evolution and
frequently ending in healing, in contrast to the more arduous evo-
lution of lesions associated with intravenous therapy.
Marx et al recommend suspending bisphosphonates
treatment for at least two months previous to an intervention.
This attempts to normalize the rate of bone turnover, owing to
the inhibitory effect of the osteoclasts and a vascular necrosis 24,43,45 44 (anti-angiogenic effect). However some authors disagree
since the bisphosphonate remains embedded in the bone tissue
for long periods of time (up to 12 years), and others consider that
a critical concentration is necessary for this oral-jaw complica-
tion to occur.64
ONJ is a clinical entity related to: an alteration of the
blood supply, an inhibition of the osteoblastogenesis, and the
apoptosis of osteocytes. All the above result in a vascular necro-
sis of the bone tissue and frequently in super infection and bacte-
37,64,65 rial colonization as well. Strains of the genus Actinomyces
have been found (specifically A. naeslundii, A. israelii).66
Overall, in order to stabilize the symptoms some au-
thors propose a conservative treatment of the lesions, continued
long-lasting antibiotic therapy, and discontinuation of bisphos- 49,51-52 phonates when possible. Other authors propose the appli-
cation of plasma rich in growth factors as an alternative therapy
in order to stimulate the angiogenesis and repair of the local
67-69 bone tissue.
Decisions should be made by a complete multidisci-
plinary team (oral and maxillofacial surgeon, oncologist, and
rheumatologist) on the basis of the current clinical stage accord-
51,70 ing to the AAOMS.
Informing the pharmacovigilance service is important
in these clinical cases in order to know the real incidence of
these lesions.
It is imperative to refer to the dentist all patients that
are going to be treated with bisphosphonates, whether orally or
intravenously, in order to eliminate possible risk factors to sub-
sequently suffer ONJ.
The authors state that they have no conflicts of interest.
The authors thank all the contributors who made possible the