ARTÍCULO ESPECIAL

 

Diagnosis, prevention, and treatment of bisphosphonate-associated osteonecrosis of the jaw. Recommendations of the Spanish Society of Oral and Maxillofacial Surgery (SECOM)

Diagnóstico, prevención y tratamiento de la osteonecrosis de los maxilares por bisfosfonatos. Recomendaciones de la Sociedad Española de Cirugía Oral y Maxilofacial (SECOM)*

 

 

L.M. Junquera, R. Martín-Granizo

* Este documento fue aprobado el día 22 de mayo del 2008, por la Comisión Científica de la SECOM, compuesta por los Dres. Acero J, Burgueño M, de Vicente JC, Martín-Granizo R, Santamaría J, Infante P, Raspall G. y López Cedrún JL.

Correspondence

 

 

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ABSTRACT

The bisphosphonates are stable inorganic pyrophosphate analogs that have demonstrated their efficacy in the treatment of a variety of pathologies, such as osteolytic lesions associated with bony metastases or multiple myeloma, malignant hypercalcemia, Paget’s disease, and osteoporosis. Currently, two disease entities supported by different degrees of scientific evidence can be characterized, at least academically: osteonecrosis associated with intravenous bisphosphonate administration and osteonecrosis associated with oral bisphosphonate administration. Prevention and treatment strategies are being consolidated for jaw necrosis associated with intravenous bisphosphonate use, but more scientific documentation is needed for the condition associated with oral bisphosphonate use. Our aim is to facilitate the clinical and complementary diagnosis of bisphosphonate associated osteonecrosis by oral health specialists (oral and maxillofacial surgeons, dentists, and stomatologists). The objectives of the present article were to describe the most appropriate preventive measures for limiting the number of cases of this pathology in the light of current knowledge, to detail the best recognized form of treatment for different stages of jaw osteonecrosis, and, for established jaw osteonecrosis, to describe good medical and dentistry practice for patients who suffer this disease or are at risk of suffering it. This document was approved by the SECOM Scientific Commission.

Key words: Bisphosphonates; Osteonecrosis of the jaw; Osteoporosis.

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RESUMEN

Los bisfosfonatos son análogos estables de los pirofosfatos inorgánicos que han demostrado su eficacia para el tratamiento de diversas patologías, como las lesiones osteolíticas asociadas a metástasis óseas o al mieloma múltiple, la hipercalcemia maligna, la enfermedad de Paget y la osteoporosis. En la actualidad se podría hablar, al menos académicamente, de dos entidades con diferentes grados de información científica: las osteonecrosis en relación con la administración intravenosa de estos medicamentos y las osteonecrosis en relación con la administración oral de los mismos. Para el primer grupo las estrategias de prevención y tratamiento empiezan a estar consolidadas, mientras que para el segundo se precisará de una mayor documentación científica para alcanzar este objetivo. Facilitar el diagnóstico clínico y complementario de las osteonecrosis por bisfosfonatos por parte de los especialistas de la salud oral (cirujanos orales y maxilofaciales, odontólogos y estomatólogos). Los objetivos del presente artículo son explicitar las medidas preventivas más apropiadas para limitar el número de casos de esta patología, a la luz de los conocimientos actuales, detallar la forma de tratamiento más reconocida para los diferentes estadios de la osteonecrosis, una vez establecida así como proporcionar un documento para la buena praxis médica y odontológica en los pacientes que padecen esta enfermedad o estén en riesgo de sufrirla. Este documento ha sido aprobado por la Comisión Científica de la SECOM.

Palabras clave: Bisfosfonatos; Osteonecrosis maxilar; Osteoporosis.

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Introduction

The bisphosphonates are stable inorganic pyrophosphate analogs that have demonstrated their efficacy in the treatment of a variety of pathologies, such as osteolytic lesions associated with bony metastases or multiple myeloma, malignant hypercalcemia, Paget’s disease, and osteoporosis. It is important that health care professionals be familiar with the different types and relative strength of the aminobisphosphonates available on the market. The principal characteristics of the drugs now authorized and their commercial names are listed in table I. However, the industry is continuously evolving. The notation in the pertinent medical record of the use of any of these drugs is the starting point for all diagnostic and prophylactic measures for bisphosphonate associated osteonecrosis of the jaw (BAONJ).

In the end of 2003 and beginning of 2004, the first cases were published in the scientific literature that showed an association between the administration of intravenous aminobisphosphonates and slowly developing exposure of the maxillary bone. Currently, two disease entities supported by different degrees of scientific evidence can be characterized, at least academically: osteonecrosis associated with intravenous bisphosphonate administration and osteonecrosis associated with oral bisphosphonate administration. Prevention and treatment strategies are being consolidated for jaw necrosis associated with intravenous bisphosphonate use, but more scientific documentation is needed for the condition associated with oral bisphosphonate use. The main differences between these two conditions are summarized in table II.

 

Risk factors

The risk factors related with the occurrence of BAONJ can be summarized as follows:

1. Patients with multiple myeloma (MM) are at greater risk of presenting BAONJ and the risk increases by 9% with every ten-year increase in age. Breast cancer is the second risk factor.

2. Patients receiving concomitant treatment with corticosteroids appear to have a greater risk of osteonecrosis.

3. Intravenous administration of bisphosphonates to patients with neoplasms, use of stronger bisphosphonates (zoledronic acid), and more prolonged use and/or higher doses are associated with a greater frequency of presentation of BAONJ.

4. Osteonecrosis usually occurs in patients who have taken oral bisphosphonates for more than three years. The mean duration of bisphosphonate use is 5.6 years (range: 3.3-10.2 years). However, some patients with intravenous bisphosphonate-associated osteonecrosis of the jaw have been treated for less than 1 year (9.3 months for zoledronic acid and 14.1 months for pamidronate).

5. In osteonecrosis of the jaw associated with intravenous aminobisphosphonates, a history of dentoalveolar surgery multiplies seven-fold the possibility of BAONJ occurrence. The presence of inflammatory oral disease (dental or periodontal) increases the possibility similarly.

6. In osteonecrosis of the jaw associated with oral aminobisphosphonate use, which is much less frequent, 50% of cases occur spontaneously (in the absence of history of dentoalveolar surgery). The primary locating is the posterior mandible.

7. The effects of intravenous aminobisphosphonates on bone can persist up to 10 years after suspending treatment.

8. The use of intravenous aminobisphosphonates for indications in which oral products are traditional used (osteoporosis, prevention of hip and vertebral fractures: Zometa, annual dose of 5 mg during three years) seems to act similarly with respect to jaw osteonecrosis as the use of oral bisphosphonates.

9. Concurrent therapies or diseases (diabetes, smoking, alcohol abuse, poor oral hygiene, chemotherapy, and others) can increase risk.

 

Objectives

1. Our aim is to facilitate the clinical and complementary diagnosis of bisphosphonate associated osteonecrosis by oral health specialists (oral and maxillofacial surgeons, dentists, and stomatologists).

2. To explain the most appropriate preventive measures for limiting the number of cases of this pathology in the light of present knowledge.

3. To detail the most recognized form of treatment for different stages of osteonecrosis once it has become established.

4. To offer guidelines for good medical and dental practice for the management of patients who suffer this disease or are at risk of suffering it.

 

Diagnostic criteria. Case definition

The following diagnostic and inclusion criteria should be considered for the purpose of differentiating bisphosphonateassociated osteonecrosis of the jaw (BAONJ) from other pathologies that course with bone exposure and delayed healing of alveolar processes (Fig. 1):

Clinical criteria

1. A patient who has received, is receiving, or formerly received intravenous or oral bisphosphonates without a previous history of irradiation of the maxillofacial region. The existence of a previous history of cervico-facial irradiation requires a meticulous differential diagnosis between osteonecrosis of physical, chemical, or mixed origin.

2. The presence of one or more ulcerated lesions with exposed upper maxillary and/or mandibular bone of more than eight weeks of evolution (AAOMS, 2006).

3. Bone exposure may be asymptomatic and self-limited in size, or accompanied by pain, growing extension, and bone sequestration (Fig. 2).

4. Some cases of BAONJ may present without frank bone exposure; in these cases, unaffiliated pain predominates, with or without small oral fistulas.

Complementary tests

1. Orthopantomography. This is the imaging technique most often used. It may not provide diagnostic information in the early stages of BAONJ (Fig. 3).

2. Computed tomography (CT) (Fig. 4). CT may allow early diagnosis and define the true extension of the osteonecrosis. It also may confirm the clinical stage and provide guidance for the specific treatment of each case. Magnetic resonance imaging (MRI) is a complementary technique for assessing the involvement of bone marrow and soft tissues.

3. Microbiologic culture and antibiotic susceptibility testing.

Histologic study. Biopsy

1. Biopsy of the exposed bone is obligatory whenever the origin of the lesion is suspected to be related to the pathology that motivated intravenous use of bisphosphonates, whether this is a primary tumor or metastasis, especially in patients with multiple myeloma.

2. In patients being treated with oral bisphosphonates, biopsy should be performed whenever there is any clinical suspicion that oral squamous-cell carcinoma is present, in accordance with the usual indications in such cases.

 

Prevention of osteonecrosis of the jaw

Intravenous bisphosphonate administration to patients with neoplasms

One of the pathogenic theories of BAONJ is that the drug is deposited in osteoclasts. This would explain why cumulative dose is a directly related risk factor and why BAONJ occurs in patients who stopped treatment years earlier. On the other hand, no cases have been published in which the drug was administered for less than 6 months. Consequently, we can assume that during the first weeks of bisphosphonate treatment the behavior of the bone is healthy and it has good regeneration capacity. We propose, therefore, that any invasive procedures that may be required in the first 3 months of bisphosphonate administration should not be contraindicated. It should be remembered that the underlying clinical situation of these patients requires immediate initiation of treatment and preventive measures must not be deferred (malignant hypercalcemia, myeloma, osteolytic metastases, and others).

Before and during the first three months of administration of intravenous bisphosphonates (AAOMS, 2007)

1. Specialists (oncologists, hematologists, gynecologists, urologists, etc.) must inform the patient and those close to the patient about the importance of maintaining oral health while receiving this treatment. The patient should be examined by a specialist in oral and maxillofacial surgery, dentist, or stomatologist before beginning treatment.

2. The oral health specialist should identify any infective foci, whether dentoalveolar or periodontal, that are present or may appear in the future, and prescribe and carry out treatment immediately. If tooth extraction is needed, the therapeutic strategy should begin at the time of this surgical act in order to establish a prudent time interval (15-20 days) between tooth extraction and the first intravenous bisphosphonate dose. Teeth with an uncertain prognosis should be removed.

3. There are no explicit recommendations that contraindicate the placement of intraosseous implants, nor have there been case reports of any association between properly osteointegrated implants and BAONJ. The insertion of dental implants before the i.v. administration of bisphosphonates is not recommended if the osteointegration period is not expected to have concluded before bisphosphonate use.

4. The dentist/stomatologist must perform all appropriate noninvasive treatments to ensure a good level of oral health and inform the patient and those close to the patient about the importance of oral health as the primary prophylactic measure against BAONJ. Conservative procedures can be performed during bisphosphonate administration.

5. The dentist should evaluate and correct a potential prosthetic trauma, especially on the lingual surfaces of the mandible. The possible presence of tori, large exostoses, and other bony prominences must be evaluated and corrected to prevent future complications, especially in patients with removable dental prostheses.

6. The dentist and medical specialist who are prescribing intravenous aminobisphosphonate treatment must inform the patient so that he or she is aware of the risks of dentoalveolar surgery once bisphosphonate treatment has been begun. The patient should also understand that the risk of BAONJ persists for a long time after bisphosphonate administration.

During intravenous bisphosphonate administration (after the first 3 months of treatment)

1. Any type of oral or dental implant surgery must be avoided.

2. If an infective focus appears, the first indication is to treat the condition with minimal periapical and periodontal trauma. Assess antibiotic coverage.

3. The dentist should regularly examine the patient’s mouth and maintain optimal oral health. Follow-up examinations at least once every six months are recommended.

After intravenous bisphosphonate administration

1. Oral surgery of any type should be avoided for a period of no less than 10 years after the last injection of bisphosphonate. Although the presence of zoledronic acid up to 12 years after administration has been demonstrated, there are no data on the topic in the reference literature and this point is still under debate.

2. The dentist must encourage the patient to be vigilant and maintain strict oral hygiene for many years.

 

Annual doses of oral or intravenous bisphosphonates (Zometa) for three years

Before oral bisphosphonate administration

1. The different specialists who prescribe treatment must inform their patients and advise them to have an oral health assessment before beginning treatment.

2. Oral health specialists have a period of 3 years to achieve an optimal state of oral health. During this period, any type of surgical and rehabilitative treatment can be undertaken. Procedures involving more bone remodeling should be performed first.

During oral bisphosphonate administration

(Due to the limited evidence currently available, recommendations for oral bisphosphonate administration should be updated regularly.)

Patients with fewer than three years of bisphosphonate administration and no risk factors

1. Oral health specialists can perform any type of surgical and rehabilitative treatment (dental implants) that proper care of the patient requires.

2. Informed consent must be obtained in which the risk of osteonecrosis of the jaw related to oral bisphosphonate use is explicitly mentioned as a risk inherent to each intervention.

3. The patient’s oral health should be followed up regularly (at least once a year).

Patients with fewer than three years of bisphosphonate administration, with risk factors: concomitant corticoid administration, age over 70 years.

1. It would be advisable, if clinical circumstances allow, to discontinue corticoid administration for a period of three months before performing any type of oral surgery.

2. Treatment may be resumed when the surgical wound has healed. In the case of dental implant surgery, a minimum period of three months is recommended.

3. The finding in fasting blood samples of serum cross-linked C-terminal telopeptide of type I collagen (b-CTx) of values above 150 pg/mL allow any type of surgery to be performed with minimal risk and without having to discontinue aminobisphosphonate use. Nevertheless, this parameter still requires more scientific evidence to confirm its validity.

4. Although surgery of the upper maxilla may have a significantly lower incidence of osteonecrosis of the jaw, this claim is pending confirmation by scientific evidence. Consequently, we cannot state that aggressive maxillary interventions do not increase the risk of BAONJ in the upper jaw.

5. Informed consent must be obtained in which osteonecrosis of the jaw related to oral bisphosphonate use is explicitly mentioned as one of the risks inherent to each intervention.

6. The patient’s oral health should be followed up regularly (at least once a year).

Patients with more than three years of bisphosphonate administration, with or without risk factors:

1. The recommendations are the same as for the patients in the previous group.

 

Treatment of established osteonecrosis of the jaw (Fig. 5)

Stage 1: asymptomatic exposure of necrotic bone without signs of infection

1.Measurement of the dimensions of the exposed jawbone, in millimeters.

2.Discuss with the prescribing specialist the possible suspension of aminobisphosphonate use.

3.Prescribe rinsing with 0.12% or 0.2% clorhexidine mouthwash every 12 hours for 15 days.

4. 15-day follow-up:

• Exposed jawbone remains the same size or is smaller than at the time of diagnosis: continue the same regimen for another 15 days.

• The size of the exposed jawbone is larger or pain or signs of infection are present: apply stage 2 treatment.

5. One-month follow-up:

• The exposed jawbone lesion has improved or resolved: advise the attending specialist that aminobisphosphonate use may be resumed if the patient’s clinical situation requires it. Apply strict prophylactic measures.

• The size of the exposed jawbone is larger or pain or signs of infection are present: apply stage 2 treatment.

Stage 2: exposed necrotic jawbone in patients with pain and signs of infection. Patients with a painful maxillary process not attributable to another cause and with radiologic signs of osteonecrosis may be included in this category. Point 1 of the following recommendations is not applicable to such cases (Fig. 6).

1. Measurement of the dimensions of the exposed jawbone, in millimeters.

2. Discuss with the prescribing specialist, if possible, the suspension of aminobisphosphonate use.

3. Prescribe rinsing with 0.12% or 0.2% clorhexidine mouthwash every 12 hours for 15 days.

4. Empirical administration of oral antibiotics (until microorganism culture and antibiotic susceptibility results become available):

• First indication: Amoxicillin/clavulanic acid 2000/125 mg every 12 hours, for 15 days. U.S. protocols: Penicillin VK 500 mg every 8 hours.

• Patients allergic to penicillin: Levofloxacin 500 mg every 24 hours, for 15 days. Alternatively: Azithromycin.

5. Administer oral nonsteroid anti-inflammatory drugs (NSAIDs).

6. 15-day follow-up:

• The size of the exposed jawbone is smaller, pain has disappeared or is diminished, and signs of inflammation and infection have disappeared: pass to stage 1 treatment.

• Symptoms persist or are worse: Continue the same therapeutic regimen for another 15 days. Order complementary studies: CT (regardless of whether or not a previous CT scan is available)

7. One-month follow-up:

• Pain has disappeared and signs of inflammation and infection have disappeared: pass to stage 1 treatment. Recommend, if the clinical situation requires it, resumption of aminobisphosphonate treatment. Apply strict prophylactic measures.

• Symptoms persist or are worse: Assess the need for stage 3 therapy.

Stage 3: exposure of necrotic jawbone in patients with pain, signs of infection, and clinical or radiographic evidence of sequestration or other complications (such as fracture).

1. Discuss with the prescribing specialist, if possible, the suspension of aminobisphosphonate use.

2. Administer oral antibiotics and clorhexidine mouthwash according to stage 2 guidelines.

3. Eliminate sequestered bone under local anesthesia, if possible. If necessary, remove the teeth involved, irrigate the surgical bed with 0.12% clorhexidine, and close the defect with resorbable material.

4. 15-day follow-up:

• Favorable evolution: suspend oral antibiotics and antiinflammatory drugs. Continue rinsing with mouthwash. Apply strict prophylactic measures for the remaining teeth. 15-day follow-up:

• Unfavorable evolution (increased jawbone exposure, intense pain, signs of infection): Continue antibiotics, mouthwash, and anti-inflammatory drugs for 15 days.

5. One-month follow-up:

• Favorable evolution: Recommend, if the clinical situation requires, resumption of aminobisphosphonate treatment. Apply strict prophylactic measures for the remaining teeth.

• Unfavorable evolution: Schedule surgery, which should consist of a conservative intervention under local anesthesia.

• Under serious circumstances in which all of the previous measures have failed, complex situations may arise in which alternative surgery may be considered. Nonetheless, any surgical interventions should be as conservative as possible:

- Pathological fracture: debridement of necrotic bone tissue and insertion of a reconstruction plate (avoid grafts).

- Osteonecrosis extending to the lower edge: block resection and insertion of a reconstruction plate (avoid grafts).

- Extraoral fistula: debridement and elimination of areas of osteonecrosis that produce mucosal irritation. The medical measures described above.

 

 

Correspondence:
R. Martín-Granizo
SECOM
C/ Corazón de María, 25 2ºE
28002 Madrid
Email: rmartin.hcsc@salud.madrid.org

Recibido: 29.05.08
Aceptado: 16.06.08

 

 

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