Bisphosphonates and Osteonecrosis of the Jaw

What is Bisphosphonates?
Bisphosphonates are drugs that are used to help prevent or control bone thinning (osteoporosis).  These drugs bind to areas where bone has been destroyed.  This slows down the damage that is caused by the cancer cells.  These drugs can also help reduce bone pain and reduce the risk of fractures in damaged bones.  There are two main methods for use of the bisphosphonates orally or by IV administration (once a month).  Here is a list of the most commonly used Bisphosphonates:

Intravenously administered bisphosphonates:

(The majority of cases seen and reported in the literature are those who were treated by IV administration)

Orally administered bisphosphonates:

(Although far less common, several cases of patients taking oral bisphosphonate also have been reported in the literature)  

What are the conditions that patients are treated with bisphosphonate?
Bisphonates medications are used for various conditions including: multiple myeloma, metastatic cancer, Paget’s disease, osteoporosis and others

What is osteonecrosis of the jaw?
The word “osteo’ means bone and ‘necrosis’ means cell or tissue death. So in simple terms, osteonecrosis means death of bone tissue.  Bone can die in any part of the body if its blood supply is compromised and the cells cannot get nutrients.

What are the factors that increase the risk of osteonecrosis of the jaw?
Although the exact causes are not known but osteonecrosis of the jaw is a seen in some patients who are exposed to any of the following conditions: 

§         Radiation therapy to the head and neck area for treatment of cancers  

§         Chemotherapy treatment   

§         Steroid therapy      

§         A history of severe periodontal disease or severe jaw infection (Poor oral hygiene)   

§         In some rare anemic patients 

§         Diabetes

§         Smoking

§         Alcohol use

§         Most recently noted in rare cases of patients who have been treated with various bisphosphonates after extraction

Here is another way to list the risk factor as described by the AAOMS bulletin:

Risk factors can be grouped as

I.                   Drug-related

II.                Local risk factors

III.             Demographic

IV.              Systemic factors.

            I. Drug-related risk factors include:

A. Potency of the particular bisphosphonate: zoledronate (Zometa®) is more potent than pamidronate (Aredia®) and pamidronate (Aredia®) is more potent than the oral bisphosphonates; the IV route of administration results in a greater drug exposure than the oral route.

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

II. Local risk factors include:

A. Dentoalveolar surgery, including, but not limited to:

            1. Extractions

            2. Dental implant placement

            3. Periapical surgery

            4. Periodontal surgery involving osseous injury

Patients receiving IV bisphosphonates and undergoing dentoalveolar surgery are at least 7-times more likely to develop osteonecrosis than patients who are not having dentoalveolar surgery.

B. Local anatomy

1. Mandible

            a. Lingual tori

            b. Mylohyoid ridge

2. Maxilla

a. Palatal tori

It has been observed that lesions are found more commonly in the mandible than the maxilla (2:1 ratio) and more commonly in areas with thin mucosa overlying bony prominences such as tori, bony exostoses, and the mylohyoid ridge.

            C. Concomitant oral disease

Patients with a history of inflammatory dental disease, e.g., periodontal and dental abscesses, are at a seven-fold increased risk for developing osteonecrosis.

            III. Demographic

            A. Age: With each passing decade, there is a 9% increased risk for BRON in multiple myeloma patients treated with IV bisphosphonates.  

            B. Race: Caucasian

            IV. Systemic factors

            A. Cancer diagnosis: Risk is greater for patients with multiple myeloma than for patients with breast cancer; and those with breast cancer have a greater risk than those with other cancers.  

            B. Osteopenia/osteoporosis diagnosis concurrent with cancer diagnosis  

What are the symptoms of osteonecrosis?

§         Jaw pain

§         Infection and swelling and exposed bone (Yellow bone in many cases) in the jaw ILLUSTRATION 1

§         Swelling and loosening of teeth ILLUSTRATION 3

§         Numbness or the feeling of heaviness in the jaw

§         Poor wound healing, resistant to antibiotic treatment in many cases ILLUSTRATION 2

§         In many cases it has occurred after extraction of teeth but we have seen occurrence of osteonecrosis in edentulous area (Under denture)  

§         Attempts at surgical correction make lesions worse

§         Occurs mainly in patients with cancer after prolonged therapy

What can I do to prevent problems?
Dental care is an important element of your overall health particularly if you were to have radiation to your jaws or were told that need chemotherapy.  Once you were diagnosed with osteoporosis, cancer or any other conditions that requires you to undergo those types of treatment you must be evaluated by your dentist. Any dental treatments including extraction of teeth must be initiated as soon as possible.   Then you need to be seen as needed and as often by your dentist for re-evaluation and oral hygiene maintenance every three (3) months.

Here is a summary of things to do:

·         Schedule a dental exam and cleaning before cancer treatment begins and periodically during the course of your treatment

·         Discuss dental procedures, such as the pulling of teeth or insertion of dental implants, with your oncologist before you start your cancer treatment

·         Be alert of changes in your mouth conditions even if you do not have any teeth in your mouth.

·         If you have dentures have your dentist check and adjust them to assure that my denture is not cutting or irritating your gum and jaw bone

·         Tell your dentist and doctor about any bleeding of the gums, pain, or unusual feeling in your teeth or gums, or any dental infections

·         Be sure to tell your regular dentist that you are being treated for cancer

·         Update your medical history record with your dentist to include your cancer diagnosis and treatments

·         Provide your dentist and your oncologist with each other's name and telephone number for consultation

·         Brushing your teeth and tongue after every meal and at bedtime, using a soft toothbrush and gentle stroke

·         Gentle flossing once a day to remove plaque (if your gums bleed or hurt, the area that is sore should be avoided, but the other teeth still should be flossed)

·         Keeping your mouth moist by rinsing often with water (many medicines cause 'dry mouth' which can lead to decay and other dental problems)

·         Avoiding use of mouthwash that contains alcohol, but you can rinse with warm salted water

·         Your dentist may prescribe a special mouth wash (Peridex- Chlorhexidine) Rinse your mouth twice daily with this mouth wash

What Types of dental treatment can I have if I am on Bisphosphonate?

1.   There is no evidence that dental filling (routine restorative procedures) has ever caused osteonecrosis. Of course drilling in the bone should be avoided if possible.  All prosthodontic appliances (dentures) should be adjusted for fit as needed.

2.   Root canal treatments (Endodontic treatments) to save your teeth are preferred over extraction of teeth, to avoid manipulation of bone and increasing the risk for bone infection. Routine endodontic technique should be used. Manipulation beyond the ends of teeth (the apex) is not recommended.

3.   Patients without gum disease (periodontal disease) should receive routine oral hygiene care using both mechanical and pharmaceutical methods to prevent periodontal disease, and should be monitored on a regular basis as determined.  Your periodontist or your dentist will provide appropriate forms of non-surgical therapy, which must be combined, with a prolonged phase of initial therapy for observation. If your periodontal condition does not resolve, surgical treatment should be aimed primarily at obtaining access to root surfaces with modest bone recontouring being considered when necessary. Without further data, guided bone regeneration or guided tissue regeneration should be judiciously considered, in view of the fact that bisphosphonates have been shown to decrease the vascularity of tissues, which may have a negative affect on grafted sites.

4.   Although we have placed thousands of dental implants in patients with bone atrophy and possibly osteoporosis but at present time with the limited data regarding the effects of implant placement in patients taking bisphosphonates we do not place dental implant in our center but your dentist may consider placing implant in selected cases and based on his or her experience. Therefore, treatment plans in patients taking bisphosphonates should be carefully considered since implant placement requires the preparation of the osteotomy site. The patient may be at increased risk for osteonecrosis when extensive implant placement or guided bone regeneration to augment the deficient alveolar ridge prior to implant placement is necessary.

5.   Prior to implant placement, the dentist and the patient should discuss the risks, benefits and treatment alternatives, which may include but are not limited to periodontal, endodontic or non-implant prosthetic treatments. As discussed above, this discussion should be documented and the patient’s written acknowledgement of that discussion and consent for the chosen course of treatment the patient’s consent should be obtained.

6.   If extractions or bone surgery are necessary, conservative surgical technique with primary tissue closure should be considered, when possible. In addition, immediately prior to and following surgical procedures involving bone, the patient should gently rinse with a chlorhexidine containing rinse (Peridex). Typically, chlorhexidine is used two times per day for two months post surgery. This can be extended to several weeks based on how the patient is healing.

7.   Prophylactic antibiotics may be utilized during the healing/wound closure phase, for procedures that involve extensive manipulation of the bone (e.g. extractions, periodontal recontouring, etc.). We place our patients on a combination of antibacterial (Amoxicillin) and antifungal (Flagyl) agents after surgical extractions for a minimum of two weeks.  In case of Penicillin allergy Zithromax or Clindamycin could be recommended as well.

The following is a modified recommendation we gathered for professional practitioners to use as a guide:                         
(modified from recommendations made by the American Association of Oral & Maxillofacial Surgeons)

Please note these are only recommendations and your dental/ Oral & maxillofacial surgeons will make their final decision based on your particular situation:

How common is Bisphosphonate induced osteonecrosis? 
In fact it is very rare!  We believe total number of potential cases in United States to be less than 3000.  A chance of you developing it is less than 1 in 100,000.  But there is no definitive method of predicting who will develop osteonecrosis at present time.

It has been reported in the literature that the median time from starting therapy to developing osteonecrosis is about 25 months.

An interesting fact is that less than 1% of the dose of an oral bisphosphonate is absorbed by the GI tract, whereas, over 50% of the dose of an IV bisphosphonate is bio-available for incorporation into the bone matrix. This may account for higher prevalence of osteonecrosis in patients taking the i.v. formulation.

How common is Osteoporosis?
Over 10 million Americans over the age of 50 have osteoporosis, while another 34 million are at risk. One out of every two women will sustain an osteoporosis related fracture (such as wrist, spine or hip) in their lifetime. It is estimated that as the population ages, the number of hip fractures in the United States could triple by 2020.

What is the role of my dentist?
Dental professionals are going to evaluate your gum and teeth looking for any pathology in the roots of your teeth, bleeding gum, exposed bone, sinus tracts, purulent periodontal pockets, severe periodontitis and active abscesses involving the medullary bone that may cause osteonecrosis. These areas should be treated immediately, because the medullary bone is already involved in the pathologic process. Some dental pathology may not be evident and generally it is recommended that the one quadrant of the jaw is treated first and observe any problems for several weeks before starting the next section of the jaw, teeth and gum (trial sextant approach). The sextant-by-sextant approach does not apply to emergency cases even if there is involvement of multiple quadrants.

Should I continue to take bisphosphonate drugs?
Bisphosphonates remain a very important part of treatment for people with some types of cancer, especially multiple myeloma and osteoporosis.  You should not stop taking your bisphosphonates unless your specialist has advised you to do so.  As you know the benefit of these drugs may exceed the rare potential complications and you must always consult with your primary physician and your specialist who prescribed the bisphosphonate to seek advice. Once again if you are having great dental health your chance of developing osteonecrosis is far less. 

How do I know if this condition is a normal healing process or osteonecrosis related to my Bisphosphonate treatment?

There are few characteristics that you must have:

1. Obviously you must have taken or are currently taking one of bisphosphonates listed in the chart above. Please make sure to tell your dentist about them even if you were taking them up to a year before your current visit.

2. Exposed bone in the jaw (what we call maxillofacial region) has persisted for more than eight weeks 

3. You have never had radiation therapy to the jaws for cancer treatment in the head and neck

References

1.       Bagan JV. Jaw osteonecrosis associated with bisphosphonates: Multiple exposed areas and its relationship to teeth extractions. Study of 20 cases. Oral Oncol 2005.

2.       Bagan JV. Avascular jaw osteonecrosis in association with cancer chemotherapy: series of 10 cases. J Oral Pathol Med 2005;34(2):120-3.

3.       Bamias A. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 2005;23(34):8580-7.

4.       Durie BG. Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 2005;353(1):99-102; discussion 99-.

5.       Ficarra G. Osteonecrosis of the jaws in periodontal patients with a history of bisphosphonates treatment. J Clin Periodontol 2005;32(11):1123-8.

6.       Gralow J. Evolving role of bisphosphonates in women undergoing treatment for localized and advanced breast cancer. Clin Breast Cancer 2005;5 Suppl(2):S54-62.

7.       Maerevoet M. Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 2005;353(1):99-102.

8.       Markiewicz MR. Bisphosphonate-associated osteonecrosis of the jaws: a review of current knowledge. J Am Dent Assoc 2005;136(12):1669-74.

9.       Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003;61(9):1115-7.

10.   Marx RE. Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg 2005;63(11):1567-75.

11.   Melo MD. Osteonecrosis of the jaws in patients with a history of receiving bisphosphonate therapy: strategies for prevention and early recognition. J Am Dent Assoc 2005;136(12):1675-81.

12.   Migliorati CA. Bisphosphanates and oral cavity avascular bone necrosis. J Clin Oncol 2003;21(22):4253-4.

13.   Migliorati CA. Managing the care of patients with bisphosphonate-associated osteonecrosis: an American Academy of Oral Medicine position paper. J Am Dent Assoc 2005;136(12):1658-68.

14.   Migliorati CA. Bisphosphonate-associated osteonecrosis of mandibular and maxillary bone: an emerging oral complication of supportive cancer therapy. Cancer 2005;104(1):83-93.

15.   Ruggiero SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004;62(5):527-34.

16.   Ruggiero SL. Practical guidelines for the prevention, diagnosis and treatment of osteonecrosis of the jaw in patients with cancer. J Oncology Practice 2006;2(1):7-14.

17.   Wang J. Osteonecrosis of the jaws associated with cancer chemotherapy. J Oral Maxillofac Surg 2003;61(9):1104-7.

18.   Woo SB. Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 2005;353(1):99-102.

19.     Zarychanski R. Osteonecrosis of the jaw associated with pamidronate therapy. Am J Hematol 2006;81(1):73-5.

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