Oral Health Group
Feature

Bisphosphonates or Other Drug-Induced Osteonecrosis of the Jaw

May 1, 2013
by Jack Zosky, DDS, FRCD(C), FICD


ABSTRACT
As an oral and maxillofacial surgeon I am often asked by referring dentists what the protocol is for dealing with patients who are taking bisphosphonate medication. These drugs are associated with what has been termed Bisphosphonate-Related Osteonecrotic Jaw (BRONJ). It is important to note that there are now additional drugs that have been implicated in the development of osteonecrosis of the jaw (ONJ). Therefore there is a move being proposed to call this surgical complication Drug-Induced Osteonecrotic Jaw or simply osteonecrotic jaw (ONJ). The “other” drugs to be aware of are monoclonal antibodies Demosumab and Bevacizumab and the multikinase inhibitor Sunitinib. These drugs are being commonly used in orthopedic and oncology fields for the treatment of osteoporosis, osteopenia, Paget disease, multiple myeloma and other metastatic malignancies. They have proved effective in preventing or at least minimizing fractures of the musculoskeletal system as well as controlling bone pain. This provides a better quality of life for these patients. However, patients do require routine dental care or emergency dental-related treatment while taking these medications that have, since Robert Marx reported in 2003, been implicated in the pathogenesis of BRONJ.

CAUSALITY
Bone resorption and apposition in a healthy patient provides for normal bone metabolic turnover and a physiologic homeostasis. Bone being laid down by osteoblastic activity is increased by the removal of bone through the osteoclastic process mediated by the parathyroid hormone and Vitamin D which must be metabolized to it’s active form called Calcitriol by certain enzymes and other mediators. Angiogenesis is important in bringing all these elements to the site of action. The bisphosphonates and Demosumab disrupt these two vital aspects of bone metabolism namely inhibition of osteoclast function as well as diminution of blood vessel growth. It has also recently been revealed that mucositis is associated with bisphosphonates so mucosal toxicity and a breakdown of the epithelial barrier can be a contributing factor. In addition, a high level of Actinomyces is routinely cultured from osteonecrotic lesions which likely represent an opportunistic infection.

Advertisement






RISK FACTORS
1. Drug-related factors:
A. Bisphosphonate Potency: I.V. route of administration using Zoledronate (Zometa) or pamidronate (Aredia) for cancer related disease presents a far greater risk for the development of ONJ than does the oral Bisphosphonate route using alendronate (Fosamax), risedronate (Actonel) or ibaudronate (Boniva).

B. Duration of therapy: Longer duration appears to be associated with increased risk.

2. Local risk factors:
A. Dentoalveolar surgery, including but not limited to:

1. Extractions

2. Dental implant placement

3. Periapical surgery

4. Periodontal surgery involving osseous injury

B. Local Anatomy–it should be noted that spontaneous development of ONJ can occur with no surgical intervention in areas with thin overlaying mucosa:

1. Mandible a) Lingual tori
                    b) Mylohyoid ridge

2. Maxilla  a) palatal tori

3. Systemic factors:
* Kidney disease (renal dialysis)
* Anemia
* Diabetes
* Obesity
* Concomitant use of other medications i.e. cancer chemotherapeutics and steroids

The following was taken from the “Position Paper on Bisphosphonate-Related Osteonecrosis of the Jaw-2009 Update”; American Association of Oral and Maxillofacial Surgeons:

TREATMENT STRATEGIES
1. Patients about to receive IV bisphosphonates:

This group of patients are at a relatively high risk of developing ONJ following dento-alveolar surgery. Therefore, if systemic conditions permit, initiation of these IV drugs should be delayed until dental health is optimized. This decision must be made in conjunction with the treating medical doctors.

Any non-restorable teeth should be extracted and any periodontal or endodontic surgery completed and IV therapy delayed, if systemic conditions permit, until surgical sites have mucosalized (14-21 days).

Patients with full or partial dentures should be examined for areas of possible mucosal trauma. Ill-fitting prostheses should be re-lined. Patients must be cautioned as to the importance of dental hygiene and regular dental evaluations and instructed to report any pain, swelling or exposed bone.

2. Patients being treated with IV bisphosphonates:
Treatment involving direct osseous injury should be avoided.

Endodontic therapy should be instituted for irreversible pulpitis or necrotic pulp.

Any facial space abscess should be incised and drained. If a tooth must be removed it should be done as atraumatically as possible.

Placement of dental implants should be avoided in the oncology patient receiving the more potent intravenous bisphosphonate medications, i.e. Aredia, Zometa, Reclast.

3. Asymptomatic patients receiving oral bisphosphonates and non-bisphosphonate therapy (Demosumab):
Duration of use is a prime factor in consideration of making a surgical decision.

1. For individuals who have taken these drugs orally for less than three years:

No alteration or delay in planned surgery is necessary. This includes any and all procedures that involve dentoalveolar osseous injury.

It is suggested that if dental implants are placed, informed consent should be provided related to possible implant failure and possible ONJ if continued use of these drugs is maintained. Such patients should be placed on a regular recall schedule.

2. Asymptomatic patients who are on these drugs for more than three years:

The prescribing medical doctor should be contacted to consider discontinuation of the medication for three months prior to surgery and three months after surgery, if systemic conditions permit—-a so-called “drug holiday”.

3. Patients taking oral bisphosphonates along with Demosumab or concomitant steroid medication:

This combination greatly increases the risk of developing ONJ. If dentoalveolar surgery cannot be avoided through endodontics or soft tissue incision and drainage then the drug holiday definitely applies. (three month prior and three month post-surgery).

4. Patients with ONJ

If exposed bone persists following dentoalveolar surgery the patient should be referred to an oral and maxillofacial surgeon. This can be a difficult condition to manage and treat. Depending on the degree of the disease treatment consists of pain control and control of the infection with chlorhexidine 0.12% rinses and appropriate antibiotics. Only minimal surgical intervention is recommended to remove any loose bone spicules. An attempt to manipulate soft tissue flaps to “cover” the exposed bone is not appropriate treatment.

The antibiotic of choice is PenVK 300 due to the prevalence of Actinomyces or if a penicillin allergy is present then Clindamycin is the drug of choice.

SUMMARY
Most patients being seen in a dental office will be on the oral form of these drugs. There is a small risk of the spontaneous development of ONJ (1 in 100,000) in these patients. But this is increased with inciting events such as dento-alveolar osseous surgery. To what degree this increases the risk of ONJ is unknown at this point. More data is required. Patients on IV administration of these drugs have a 3 to 12% chance according to various literature reports of developing spontaneous ONJ. This is significantly increased following osseous injury to a far greater degree than patients
taking the oral form of the drug. Informed consent should be obtained.

I would add that a Canadian ONJ task force recently met in San Diego in conjunction with the American society for Bone and Mineral Research with representation from General Dentistry, OMF Pathology, Rheumatology, Endocrinology, Radiology and Gynecology.

A Canadian registry has been established for ONJ patients for data collection in attempts to learn more about this disease. If you suspect a patient has ONJ email this information to ONJ@dal.ca

1. Get a simple verbal informed consent from the patient to be contacted by the Registry.

2. Take a clinical photograph and email it along with a radiograph.

3. Send patient contact information including name, postal address, phone number and email.

4. If a patient fails to consent just let the registry know another case of ONJ had occurred.

All reference material related to the article is from the American Association of Oral and Maxillofacial Surgeons Position Paper on Bisphosphonate-Related Osteonecrosis of the Jaw-2009 Update and can be accessed by going to the AAOMS web site www.aaoms.org and highlighting Bisphosphonate TherapyPprotocol.OH