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BISPHOSPHONATES AND ORAL HEALTH

 

Patients who have been receiving IV bisphosphonates should avoid
having teeth pulled at all costs

Attention!

  Prevention is the key:  PRETREATMENT phase before the
patient begins chemotherapy with one of these drugs is probably the MOST
important stage in preventing future complications of osteonecrosis.
The dentist can have the most significant effect of prevention by
performing any invasive dental procedure before they begin treatment

                

 

Update on Bisphosphonates and Osteonecrosis of the Jaws

Overview-Newest ADA Recommendations

Reports of bisphosphonate-associated osteonecrosis of the jaw (BON) associated with the use of Zometa (zolendronic acid) and Aredia (pamidronate) began to surface in 2003. The majority of reported cases have been associated with dental procedures such as tooth extraction; however, less commonly BON appears to occur spontaneously in patients taking these drugs1. Zolendronic acid and pamidronate are intravenous (i.v.) bisphosphonates used to reduce bone pain, hypercalcemia and skeletal complications in patients with multiple myeloma, breast, lung and other cancers and Paget’s disease of bone.

Several cases of BON have also been associated with the use of the oral bisphosphonates, Fosamax (alendronate), Actonel (risedronate) and Boniva (ibandronate), for the treatment of osteoporosis; however, it is not clear if these patients had other conditions that would put them at risk for developing BON.2

The table below lists all oral and i.v. bisphosphonates currently on the market in the U.S.Please see your doctor BEFORE you have an extraction

Orally Administered Bisphosphonates
Brand Name Manufacturer Generic Name
Actonel Procter & Gamble Pharmaceuticals risedronate
Boniva Roche Laboratories ibandronate
Fosamax Merck & Co. alendronate
Fosamax Plus D Merck & Co. alendronate
Skelid Sanofi Pharmaceuticals tiludronate
Didronel Procter & Gamble Pharmaceuticals etidronate

 

Intravenously Administered Bisphosphonates
Brand Name Manufacturer Generic Name
Aredia Novartis pamidronate
Zometa Novartis zolendronic acid
Bonefos Schering AG clodronate

 

Symptoms

The typical clinical presentation of BON includes:

bulletpain,
bulletsoft-tissue swelling
bulletinfection
bulletloosening of teeth
bulletdrainage
bulletexposed bone3.

These symptoms may occur spontaneously, or more commonly, at the site of previous tooth extraction. There may also be feelings of numbness, heaviness and dysesthesias of the jaw. However, BON may remain asymptomatic for weeks or months, and may only become evident after finding exposed bone in the jaw.

Dental Management

It is important to understand that, based on the information currently available, the risk for developing BON is much higher for cancer patients on i.v. bisphosphonate therapy than the risk for patients on oral bisphosphonate therapy. Therefore, there are different recommendations for dental management.

For patients on oral bisphosphonate therapy
The risk of developing BON  on oral bisphosphonate therapy appears to be very low;4 however, though the risk is small, currently millions of patients take these drugs. Therefore, recommendations for dental management of those on oral bisphosphonate therapy | PDF file/159k Link opens in separate window. Pop-up Blocker may need to be disabled. NEW! were developed by an expert panel assembled by the ADA’s Council on Scientific Affairs.5 These panel recommendations focus on conservative surgical procedures, proper sterile technique, appropriate use of oral disinfectants and the principals of effective antibiotic therapy. There is currently no data from clinical trials evaluating dental management of patients on oral bisphosphonate therapy, and therefore, these recommendations are based on expert opinion only. A comprehensive oral evaluation is recommended for all patients about to begin therapy with oral bisphosphonates. These recommendations do not address treatment of patients on i.v. bisphosphonate therapy or patients with BON.

For patients on i.v. bisphosphonate therapy
While on treatment, invasive dental procedures should be avoided in patients receiving i.v. bisphosphonates.

The prescribing information for these drugs recommends that cancer patients:

bulletReceive a dental examination prior to initiating therapy with intravenous bisphosphonates (Aredia and Zometa); and
bulletAvoid invasive dental procedures while receiving bisphosphonate treatment. For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition. Clinical judgment by the treating physician should guide the management plan of each patient based on an individual benefit/risk assessment.

If you have a history of multiple myeloma, metastatic cancer, Paget’s disease and osteoporosis  you may need to check to see if you  received i.v. bisphosphonates during treatment. In addition, it may be important to know of any history of i.v. bisphosphonate administration, because these drugs have a long half-life (years).6

An expert panel convened by Novartis Pharmaceuticals Corporation (the manufacturer of Zometa and Aredia) in 2004, made the following recommendations for prevention, diagnosis and treatment of osteonecrosis of the jaw in patients on i.v. bisphosphonate therapy:3,7

bulletPatients should be educated on maintaining excellent oral hygiene to reduce the risk of infection.
bulletDentists should check and adjust removable dentures to avoid soft-tissue injury.
bulletRoutine dental cleanings should be performed with care not to inflict any soft-tissue injury.
bulletDental infections should be managed aggressively and nonsurgically (when possible).
bulletEndodontic therapy is preferable to extractions; and, when necessary, coronal amputation with root canal therapy on retained roots to avoid the need for extraction.
bulletSee our Medical History addressing this issue: Bisphosphonate History

For patients with BON
Recommendations for the treatment of patients with BON have been published7 and are posted on the Web site for the Journal of Oncology Practice Link opens in separate window. Pop-up Blocker may need to be disabled..

Obtaining Informed Consent Is recommended by the ADA.

http://www.ada.org/prof/resources/pubs/jada/patient/patient_64.pdf-handout for patients on BON

3/08

7/06

Endnotes

  1. Woo S-B, Hande K, Richardson PG. Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 2005;353:100 Link opens in separate window. Pop-up Blocker may need to be disabled..
  2. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: A review of 63 cases. J Oral Maxillofac Surg 2004;62:527-34 Link opens in separate window. Pop-up Blocker may need to be disabled..
  3. Expert Panel Recommendations for the Prevention, Diagnosis, and Treatment of Osteonecrosis of the Jaws: June 2004 | PDF file/56k Link opens in separate window. Pop-up Blocker may need to be disabled..
  4. Migliorati CA, Casiglia J, Epstein J, Jacobsen PL, Siegel MA, Woo S-B. Managing the care of patients with bisphosphonate-associated osteonecrosis: An American Academy of Oral Medicine position paper. JADA 2005;136:1658-68 Link opens in separate window. Pop-up Blocker may need to be disabled..
  5. ADA Council on Scientific Affairs. Expert Panel Recommendations: Dental Management of Patients on Oral Bisphosphonate Therapy. June 2006 .
    | PDF file/159k Link opens in separate window. Pop-up Blocker may need to be disabled. NEW!
  6. Ott SM. Long-term safety of bisphosphonates. J Clin Endocrinol Metab 2005;90:1897-9.
  7. Ruggiero S, Gralow J, Marx RE, Hoff AO, Schubert MM, Huryn JM, Toth B, Damato K, Valero V. Practical Guidelines for the Prevention, Diagnosis, and Treatment of Osteonecrosis of the Jaw in Patients With Cancer. J Oncol Prac 2006;2:7-14 Link opens in separate window. Pop-up Blocker may need to be disabled..

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Lastest Recommendations:

Dr. Yamashita at USC has developed an Osteonecrosis test. The CTX test is done at only one lab in the US-Quest Diagnostics in San Juan Capistrano, CA  It is done only for those who have been on ORAL bisphosphonates.

Results
<100 pg/ml=High Risk
100-150=Moderate Risk
>151=Little to No Risk

Dr. Marx's recommendation:
-if on an oral bisphosphonate for <3 yrs, treat as necessary.
-if on oral for >3 yrs, he advocates discontinuing it for 3 months prior to the planned procedure and send for CTX testing.  Once treatment is done, extend the "drug holiday" for an additional 3 months.

That's as "definitive" as of information we have at this time. Again, here is the link to the two presentations Dr. Marx will be doing here in the US, one in CA this month, and another in Chicago in July.  http://www.meccinc.com/74209_Oral%20Intravenous%20BrochFINAL.pdf
IDF 3/07

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Treatment drug may cause jawbone to die

Breast cancer patients, individuals at risk for osteoporosis, and individuals undergoing certain types of bone cancer therapies often take drugs that contain bisphosphonates. Bisphosphonates may place patients at risk for developing osteonecrosis of the jaws (a rotting of the jaw bones), according to  May/June 2006 issue of General Dentistry, the Academy of General Dentistry’s (AGD) clinical, peer-reviewed journal.

Bisphosphonates are a family of drugs used to prevent and treat osteoporosis, multiple myeloma, Paget’s disease (bone cancers), and bone metastasis from other cancers. These drugs can bond to bone surfaces and prevent osteoclasts (cells that breakdown bone) from doing their job.

“Healthy bones constantly rebuild themselves, however, since the jawbones have rapid cell turnover, they can fail to heal properly in patients taking any of the bisphosphonate drugs. Patients need to be aware of the possibility of complications from dental surgery or extractions.” Since these drugs linger in the bone indefinitely, they may upset the cell balance in how the jaws regenerate and remove unhealthy bone.

In their report, the authors refer to the case of a woman who received bisphosphonate therapy intravenously to treat metastatic breast cancer. She then developed osteonecrosis in her upper and lower jaws following tooth removal.

“This type of osteonecrosis has been occurring since the advent of these drugs, at this time osteonecrosis as a result of bisphosphonate therapy has no treatment.”

Patients who are taking bisphosphonates should inform their dentist to prevent complications from dental surgical procedures. “By informing your dentist that you are taking a bisphosphonate, different avenues for treatment can be explored,."

It is strongly recommended that patients scheduled to receive bisphosphonate therapy should visit a dentist or an oral surgeon so problematic teeth can be treated prior to the start of therapy”.

“Widespread use of bisphosphonates to prevent or treat early osteoporosis in relatively young women and the likelihood of long-term use is a cause for concern,, how bisphosphonates interfere with healing after dental surgery is still unclear and further research will be needed. It is imperative that the public understands there is no present treatment or cure for this problem.”

Tips to reduce the risk for osteonecrosis of the jaw and maintain a healthy mouth:
Inform your general dentist or specialist if you are taking bisphosphonates.
•Check and adjust removable dentures.
•Obtain routine dental cleanings.
•Opt for root canal therapy over extractions when possible
. AGD 8/06

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Remember if you are on or have taken  or will take bisphosphonates:

         You should receive a dental examination prior to initiating bisphosphonate therapy

         You should complete any  necessary major dental procedures (e.g., tooth extraction or (surgical placement of)) dental implants prior to initiating bisphosphonate therapy.

         You  should be encouraged to practice good oral hygiene and minimize possible jaw trauma;…minimize sharp edges on dentures and…ensure proper fit.

          You should avoid dental surgery during treatment with bisphosphonates.     

           And if you have taken  a bisphosphonate drug, avoid chewing things that can cause oral “puncture wounds,” such as pretzel sticks or potato chips.   It’s not worth the risk of injury to bone......we have a friend who has gone undergone extensive medical treatment because she has been taken Fosamax and some food item caused an injury to her mouth and she now has osteonecrosis.

11/06

Reference Help

Therefore, I would advise  you to continue treating patients on oral bisphosphonates with an appropriate informed consent. For  elective surgery and with the approval of their endocrinologist it is ideal to  discontinue the oral bisphosphonate for 3 months before and after
surgery,  particularly if they have been taking an oral bisphosphonate for 3 years or more  and /or they have other co morbidities affecting wound healing. Any drug that inhibits osteoclast  function has the potential to cause ONJ. It is a matter of cellular  toxicity, dose, duration of therapy, and reversibility.

Vishtasb  Broumand, DMD, MD Oral & Maxillofacial Surgery Head and Neck Tumor  and Reconstructive Surgery
Florida Oral  and Facial Surgical Associates 549 Health  Boulevard Daytona  Beach, FL 32114
Office: (386)  252-6438  Fax: (386) 258-1989

Adjunct  Assistant Professor of Clinical Surgery Division of Oral & Maxillofacial  Surgery University of Miami School of Medicine/ Jackson Memorial  Hospital 9380 S.W. 150th Street, Suite 170 Miami, FL  33157 Office: (305)  256-5270  Fax: (305) 256-5280 IDF 8/06

 

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Some thoughts : Remember how little we actually know about this problem right now.
 
bulletNo matter what your age now is the time to increase calcium intake, increase exercise and healthy life style choices, build bone mass now to prevent problems later
bulletI have not personally recommended that my wife take bisphosphonate for prevention of osteoporosis remember these drugs have long half lives.
bulletConsider looking at nonbisphosphonate such as Evista and HRT.
bulletFor cancer patients who will be placed on IV bisphosphonates please have restoration of dental health PRIOR to beginning these drugs or prior to beginning chemotherapy or XRT.
bulletPlease discuss these issues with your health care provider who is suggesting or prescribing bisphosphonates for the best decision for your individual case.

IDF 7/06

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Recommendations by Our Area Dental Professionals:

Most of the adverse events have occurred in patients taking intravenous bisphosphonates such as Pamidronate (Aredia) and Zolendronate (Zometa).  However the oral bisphosphonate Alendronate (Fosamax) has also been implicated in a few cases.  Patients taking the intravenous forms are usually being treated for cancer, while most patients on Fosamax are taking it for osteoporosis.  The osteonecrosis usually presents as an area of exposed, necrotic bone that may or may  not be painful.  The reason for this effect being limited to the jaws is probably due to the fact that the higher turnover rate of bone in the jaws can concentrate the bisphosphonate.

The mechanism of action underlying this side effect is not completely clear but two theories seem to present the strongest cases.  First, bisphosphonates have been found to be antiangiogenic.  The second proposed mechanism is based on osteoclast inhibition, which is the primary mechanism of action for these drugs.  If necrotic bone cannot be resorbed by the osteoclasts in the course of normal healing, then the necrotic bone will inhibit healing and affect blood supply to the area. Precipitating factors associated with the osteonecrosis include dental extraction, severe periodontitis, spontaneous exposure, periodontal surgery, dental implants and root canal surgery, in that order of prevalence.

Current recommendations include completion of needed or anticipated dental work prior to beginning bisphosphonate therapy, especially for the IV cases.  This is similar to the protocol recommended for patients requiring radiotherapy for head and neck.  The difference is that radionecrosis responds to hyperbaric therapy, bisphosphonate related osteonecrosis does not.  This is the most importnat concept for intravenous cases. Other suggestions include performing coronectomies rather than extractions in these patients and dental implants are not recommended.  It has been recommended by Dr. Geoff Engelhardt's article that a rinse of Chlorhexidine follow extractions

Some research has found that patients taking Fosamax for less than three years require no alteration in treatment.  In those on the drug for over three years it is recommended that patients discontinue oral Alendronate for three months, complete their dental care, then start the Fosamax three months after care is completed.  This may rise some questions as the effective time of osteoclast inhibition is around ten years.

If you develop osteonecrosis of the jaws, please see an oral surgeon immediately.  Treatment may involve sequestrectomy of the necrotic bone, but success rates for this treatment vary.  Another treatment option may be a regimen of antibiotics followed by regular rinse with 0.12% Chlorhexidine.  A 91% success rate has been recorded with this regimen in eliminating pain though exposed bone remains.

The risk in Fosamax users is extremely low but exists, so the protocol recommended should be followed to protect your patients.

Periodontal Associates, Dr. Lindeberg and Dr. Johnson 5/06 newsletter.

Talk to your dentist BEFORE you have dental surgery if you are taking  Fosamax

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 Dental treatment for patients currently receiving bisphosphonate therapy
·        Maintain excellent oral hygiene to reduce the risk of dental and periodontal infections
·        Check and adjust removable dentures for potential soft-tissue injury, especially tissue overlying bone.
·        Perform routine dental cleanings, being sure to avoid soft-tissue injury
·        Aggressively manage dental infections nonsurgically with  root canal treatment if possible or with minimal surgical  intervention.
·        Endodontic (root canal) therapy is preferable to extractions when possible. It may be necessary to carry out coronal amputation with subsequent root canal therapy on retained roots to avoid the  need for tooth extraction and, therefore, the potential development of osteonecrosis.

Osteonecrosis of the jaws is seen mainly with drugs such as Zometa or Aredia which are  bisphosphonates given to reduce hypercalcemia seen in certain cancers. A recent study done by UCLA/VA indicates that patients getting IV Fosamax have a higher  incidence of failure to achieve integration with dental implants than patients who are  not taking bisphosphonates or are taking them orally. One problem with the bisphosphonates is that they persist in bone for very long periods  of time, so discontinuing use may not be effective.

Appendix 11:Expert Panel Recommendation for the Prevention,Diagnosis and Treatment of Osteonecrosis of the Jaw
http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4095B2_02_12-Novartis-Zometa-App-11.htm

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Braces-Considerations:

Ortho is near impossible, apparently the whole replacement and resorbtion cycle is disrupted.

How long does ones have to be off these medications?

How long does a one have to be off these meds to rid their system of the effects of this medication....some reports are talking about ten years or more. IDF 4/06  

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How does this occur:

Bisphosphonates inhibit bone removal (resorption) by osteoclasts, thereby supporting the buildup of new bone. While this action may help prevent fractures in the hip, spine and other skeletal regions, it may disrupt the osteoclast/osteoblast axis in the jaws, impairing osteoclasts' ability to remove, and thus repair or contain, 'diseased' bone.
This impairment then causes osteoblasts to "overbuild" or "wall off"diseased bone. As osteoblasts build new bone, the failure of osteoclasts to remove contaminated bone interferes with the  development of the necessary structure, or 'scaffolding,' on which to lay down healthy bone.

T American Association of Oral and Maxillofacial
Surgeons Bisphosphonates Can Wreak Havoc in the Mouth and Jaws, Oral and Maxillofacial Surgeon Warns
http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=109&STORY=/www/story/05-05-2005/0003545338&EDATE=

Hyperbaric O2 promotes periosteal blood supply to the bone. The bisphosphonates irreversibly alter the metabolism of the osteoclasts and so you get no or very poor bone resorbtion even if the blood supply is good.

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News Updates

Please talk to your doctor about bisphonates. Some bisphonates, like tamoxifen, are given by injection to help guard against breast cancer recurrence.  Others like Fosamax are given orally to help prevent and treat osteoporosis. It has been observed within the last few year that there is a relatively uncommon but potentially serious effect of bisphonates, especially with the injectable forms. A complication known as osteonecrosis, literally, dissolving of bone, can occur after surgical procedures such as tooth extractions.  This appears to occur with unusual frequency in people taking bisphonates.  This post-treatment condition is uncommon, but the research on it is in its infancy, so we can’t really say exactly what the risk is statistically. Talk to your physician if you’re taking or thinking of taking a bisphonate, especially Fosamax.  These drugs are absorbed by bone and stay in the bone a long time, perhaps years after you stop taking the drug.   Ask questions and make an informed decision on whether it’s right for you to take a bisphonate.  If you’re considering any surgery, dental or medical, it’s important that you inform the surgeon if you’re taking this medication.7/06
 

Bisphosphonates, including alendronate (Fosamax®), and ONJ
 

It is recommend that the least  possible infection and trauma to the jaws of anyone on a  cancer-related bisphosphonate for more than 6 months. Relative to  implants, that would tell me that they should not be done in these patients. The Panel will also recommend not stopping the cancer-related bisphosphonates unless there is exposed alveolar bone.2/06

Bisphosphonates and osteonecrosis of the jaw

FDA Advisory Comments on Bisphosphonates

Understanding the pathophysiology of osteoporosis requires knowledge of the basic process of bone remodelling, a process that occurs in all bones, throughout life. At any given time, most bone units are in a resting stage, metabolically quiescent. When the remodelling process is initiated, osteoclasts are activated, and bone resorption occurs, resulting in loss of bone substance. This phase typically lasts two or three weeks. The
process is reversed with the action of osteoblasts, which lay down new bone matrix, which is in turn mineralized. The active phase of bone deposition and mineralization usually takes two or three months.

In osteoporosis, the central pathophysiological defect is increased bone turnover, leading to skeletal fragility and increased risk of fracture
through two mechanisms. An uncoupling of the remodelling process occurs, with bone resorption being greater than bone formation, leading to net loss of bone, low bone mass, and thus increased risk of fracture. However, at the same time, there is a more subtle change. Bone resorption specifically weakens trabeculae, with trabecular strut perforation. On a microarchitectural basis, this loss of mechanical support directly leads to skeletal fragility and thus increased fracture risk.

Osteoporosis is defined as a progressive systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of
bone tissue, leading to increased bone fragility and risk of fracture. Both the negative effects of increased bone turnover, and of remodelling
imbalance, is typical in osteoporosis. High bone turnover (because of increased frequency of activation of the remodelling sequence) means that at any given time, more bone pits can be found, decreasing biomechanical strength. At the same time, the imbalance in remodelling means that less bone is laid down than was removed. Both of these processes � increased bone turnover, and negative bone balance � leads to rapid loss of bone in osteoporosis.

The diagnosis of osteoporosis is clear in a patient with progressive deformity from vertebral fractures. Some of the physical sequelae of
severe osteoporosis include: increasing number and severity of vertebral fractures; loss of overall height; presence of a dorsal kyphosis
(dowager�s hump); protruberant abdomen; crowding of the ribs and; reduction in lung volume. These changes are commonly preventable with appropriate treatment, which includes the class of medications known as the bisphosphonates.

The Bisphosphonates are indicated for:

- Prevention and treatment of osteoporosis
- Treating Paget's disease of bone
- Hypercalcemia associated with malignancy
- Osteolytic lesions associated with metastatic bone disease
- Multiple myeloma

They act as bone resorption inhibitors increasing bone density by binding to the bone matrix and slowing down osteoclastic activity, thereby
facilitating osteoblastic effectiveness.

Inorganic pyrophosphates are orally inactive, as they are hydrolyzed in the GI tract. The bisphosphonates were developed to circumvent this
limitation, and are effective agents when administered orally (although they are all poorly absorbed, and should be taken while fasting). They are not metabolized significantly. Absorbed drug that is not bound to bone is excreted unchanged by the kidneys. Bisphosphonates also have a high affinity for calcium, and bind strongly to bone mineral, hydroxyapatite, especially at sites of bone resorption where mineral is most exposed. The bisphosphonate is absorbed by osteoclasts, and suppresses osteoclast function � osteoclast apoptosis is also enhanced.

The action of bisphosphonates that should concern dentists is that they destroy osteoclasts, without which there cannot be bone healing. In fact, it was reported in the literature last year that:

"Osteonecrosis of the Jaw (ONJ) has been reported in patients with cancer receiving treatment including bisphosphonates, chemotherapy, and/ or corticosteroids. The majority of reported cases have been associated with dental procedures such as tooth extraction. A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors. While on treatment, these patients should avoid invasive dental procedures if possible. No data is available as to whether discontinuation of bisphosphonates therapy reduces the risk of ONJ in patients requiring dental procedures." (http://www.us.zometa.com/hcp/safetyinformation.jsp)

Osteonecrosis of the jaw is also known as avascular necrosis of the bone or osteochondritis dissecans (the death of bone resulting in the collapse of the bones' structural architecture). It leads to bone pain, loss of bone function, and bone destruction and is the result of a number of conditions leading to an impairment of the blood supply to the bone.

As stated in the "Dear Doctor" letter from Novartis, bisphosphonates are used to treat several other conditions related to bone metabolism and neoplasms. What is not known yet is whether the osteoclasts ever come back. Unlike osteoradionecrosis, this condition is not helped by
hyperbaric O2 therapy. There is also some preliminary evidence that discontinuation of certain bisphosphonates does not seem to help.

As mentioned above, there are two forms of bisphosphonates, one with a chloride ion for oral use that is "relatively" benign (eg. Fosamax). Oral surgery for patients taking these is risky, at least requiring extensive informed consent, not that there is good or sufficient information yet. The other form with a nitrogen ion is used IV and is probably an absolute contraindication to tooth extraction. The suggested alternative is to cutoff the tooth crown, do endo and let the tooth extract itself over time.

In 2003 and 2004, there were several reports of osteonecrosis of the jaw (ONJ) in cancer patients receiving chronic intravenous bisphosphonates. The reports associated pamidronate (Aredia) and zoledronic acid (Zometa) with ONJ.  Both products are produced by Novartis Pharmaceuticals Corporation.  As a result, the products' labeling was updated in the U.S. in August 2004 and in Canada in December 2004 to include precautions about ONJ (see quote above from website).  Novartis is not the only company marketing these drugs, there are at least five of these drugs in use. With so many patients taking bisphosphonates for prevention and treatment of
osteoporosis he thinks we will start to see this complication with increasing frequency.

Risk factors include systemic corticosteroid therapy and anti-cancer treatment (both radiation and chemotherapy). The jaw bone is particularly vulnerable to osteonecrosis because of tooth and gum susceptibility to infection. A special added risk factors for ONJ are trauma, as from dental procedures, and local anesthetics.

In a 2004 report from the FDA Adverse Event Reports database a total of 139 cases of osteonecrosis were identified from the marketing approval date of Aredia, Zometa, Fosamax, and Actonel until May 24, 2004:
� 34% were associated with Aredia
� 24% per associated with Zometa
� 42% per associated with patients who received both Aredia and Zometa
� 8.6% were associated with Fosamax
� one case was associated with Actonel.

The majority of these patients were diagnosed with osteonecrosis of the jaw.  Some had a diagnosis of mixed osteonecrosis and osteomyelitis. Because of these findings, the report stated that osteonecrosis may be a class effect of the bisphosphonates.  The oral bisphosphonates are not as potent as the intravenous agents but they all have the same mechanism of action. Labeling for both Fosamax and Actonel is in the process of being updated to include this class osteonecrosis risk. Boniva labeling already has been updated.

Conclusions to be drawn from all of this evidence to date indicates that the majority of cases with osteonecrotic jaw lesions occurred after a
dental extraction yet some occurred spontaneously. Because of this association with dental procedures, potential preventative measures are
suggested prior to bisphosphonate initiation.

Preventative measures include:
� Avoiding any elective jaw procedure
� Baseline and routine dental exams including panoramic jaw radiography
� Delaying bisphosphonate therapy, if risk factors allow, to complete dental  procedures for teeth or dental structures with poor prognosis
� Educating patients about the importance of good oral hygiene, symptom reporting, and regularly scheduled dental assessments

Patients already receiving bisphosphonates should:
� Maintain excellent oral hygiene and have routine dental examinations
� Obtain routine dental cleanings where careful attention is given to avoiding soft tissue injury
� Have aggressive nonsurgical management of any dental infection
� Have root canal treatment if needed rather than dental extraction when possible

Use of hyperbaric oxygen is commonly done IF necrosis begins.  Has been pretty successful for radionecrosis but much less so for necrosis following the bisphosphonates.


Remember, the majority of cases with osteonecrotic jaw lesions occurred after a dental extraction yet some occurred spontaneously. Patients with osteonecrosis or suspected osteonecrosis should receive immediate attention from an oral surgeon or dental oncologist. Also, suspected
problems associated with bisphosphonates should be reported:

"Osseointegrated dental implants are contraindicated and may result in further osteonecrosis".

In the US, call the FDA MEDWATCH program at 1-800-FDA-1088 or go on-line to www.fda.gov/medwatch.

In Canada, call the Canadian Adverse Drug Reaction Monitoring Program at 1-866-234-2345 or go on-line to
http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/adverse_e.pdf.

References for the above information include:

Assouline-Dayan Y, Chang C, Greenspan A, et al. Pathogenesis and natural history of osteonecrosis. Semin Arthritis Rheum 2002;32:94.

Department of Health and Human Services, Public Health Service, Food and Drug Administration, Office of Drug Safety, Postmarketing Safety Review. August 25, 2004.
http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4095B2_03_04-FDA-TAB3.pdf. (Accessed April 14, 2005).

Anon. Expert panel recommendation for the prevention, diagnosis and treatment of osteonecrosis of the jaw. appendix 11. Oncologic Drug Advisory Committee Meeting. Novartis Pharmaceuticals Corporation. EastHanover, NJ 07936. March 4, 2005. 10/05

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There is no consensus on how to manage this condition, especially when extractions are unavoidable, as in this case.  What I can say is that the international literature agrees on a few things.
1. Avoid surgery (extractions) in these patients, if possible (implants included by inference).
2. If teeth have to be removed and complications develop, these are best managed conservatively - once again, avoid the temptation to open, debride & drain.
3. The risk of osteonecrosis is greater with parenteral bisphosphonates used in the treatment of myeloma, etc. but there is a risk with the oral meds.
4. Withdrawing the medication before/during/after surgery is not thought to make any difference to the outcome.
10/05
Dr Zaf Khouri Dental Surgeon & Consultant Forensic Odontologist 1100 Victoria Street PO Box 464 Hamilton NEW ZEALAND

Cancer patients receiving intravenous bisphosphonate drugs should not be treated with invasive dental procedures. Novartis Pharmaceuticals Corp. stated that osteonecrosis of the jaw (ONJ) has been observed in cancer patients who are receiving Aredia or Zometa-bisphosphonates used to treat complications of advanced cancer known as "hypercalcemia of malignancy," bone metastases from solid tumors and other conditions ADA Updates 6/05

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Research:
"Bisphosphonates have a long residence time in bone. The terminal half-life  of alendronate is approximately 10 years (3), and alendronate will  therefore accumulate in bone for up to three half-lives, or 30 years.
Inhibition of bone resorption is sustained for at least five years after  cessation of alendronate therapy (16;17), illustrating that alendronate  released from the matrix during bone remodeling effectively inhibits  osteoclasts. If inhibition of bone resorption is proportional to the sum of  the recently administered alendronate dose plus previously administered  alendronate that is released from the matrix, as proposed (3), then over  time, as alendronate release from saturating bone matrix stores continues  to increase, bone resorption rates could slow eventually to dangerous  levels. The release of alendronate from bone matrix after 10 years of 10  mg/day is estimated to be equivalent to 2.5 mg/day orally (3).""The  mineralization of bone increases during bisphosphonate therapy (19;20). The  primary phase of mineralization of newly formed bone takes weeks, but the  secondary phase occurs over years. As bone remodeling slows, the net age of  existing bone increases, allowing more time for secondary mineralization to  take place. Increased tissue mineral content (rather than a remodeling  transient or a true increase in the ratio of bone volume to total volume)  is largely responsible for the sustained increases in BMD during  bisphosphonate therapy (20). As tissue mineral content increases, bone
becomes tougher and is protected from fracture, but bisphosphonates at high  doses produce highly mineralized and homogeneous bone that is brittle and  aubject to microfracture damage (21). Preliminary reports indicate that  after five years of risedronate (22) or 10 years of alendronate treatment  (18), tissue mineral content, on average, is in the normal premenopausal rangeabout where one might want it. The effects of longer term accumulation  are unknown, however. High-dose intravenous bisphosphonate therapy of  cancer-induced bone disease has recently been associated with osteonecrosis  of the jaw (23;24). Most patients were also receiving chemotherapy or  corticosteroids, and without good case-control data, the role of  bisphosphonates in this complication is impossible to establish. We are  aware of a number of unreported cases, however, suggesting that the  complication is not rare in cancer patients treated with bisphosphonates.  In one study, six of 63 patients with osteonecrosis of the jaw were  receiving oral bisphosphonates for treatment of osteoporosis (24). It seems  likely to us that jaw osteonecrosis is a dose-related side effect of  bisphosphonate therapy that is rare in the oral dose range and more common  with intravenous bisphosphonate use. Good case control studies are necessary to confirm or refute this interpretation and define risk factors  for osteonecrosis; duration of oral bisphosphonate therapy and cumulative
 ose will be an important consideration."

The International Bone and Mineral Society. Long-Term Bisphosphonates for Osteoporosis: An Introduction Gordon J.  Strewler Beth Israel Deaconess Medical Center and Harvard Medical School,  Boston, MA, USA  BoneKEy-Osteovision. 2005 January;2(1):6-9
http://www.bonekey-ibms.org/cgi/content/full/ibmske;2/1/

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Jaw Surgery Failure

Over a three-year period, the jaws of dozens of patients who had undergone oral surgery at his hospital had failed to heal properly. Part of the jawbone had died and become exposed. "We never saw this before in the jaw" except in patients who had received radiation therapy to that part of the face.

Further investigation revealed one common thread: All of the patients had been treated with at least one of a class of drugs called bisphosphonates. Most were cancer patients who had received the intravenous bisphosphonates Zometa or Aredia or both for excessive calcium in their blood or bone tumors. But about 10% were osteoporosis patients who had taken an oral bisphosphonate, mainly Fosamax.

Ruggiero co-wrote a report on 63 patients with osteonecrosis - or bone death - of the jaw in the Journal of Oral and Maxillofacial Surgery. Six had taken Fosamax, and a seventh had taken Actonel, another oral bisphosphonate for osteoporosis. The problem doesn't appear to be as severe with oral bisphosphonates as it is with the IV drugs. Patients who have been receiving IV bisphosphonates should avoid having teeth pulled "at all costs," Based on his cases, a Food and Drug Administration (news - web sites) Web site suggests that osteonecrosis of the jaw (ONJ) is a risk of all bisphosphonates, not just the IV drugs.

Bisphosphonates remain in bone indefinitely. Ruggiero speculates that their long-term use could upset the delicate balance between cells that put calcium in bone and cells that take calcium away. The FDA (news - web sites) review concluded that all bisphosphonate labels should mention osteonecrosis.

Rugierro says he has now seen a total of 12 or 13 cases of ONJ in patients treated with an oral bisphosphonate. Robert Marx, chairman of the division of oral and maxillofacial surgery at Florida's University of Miami, says he's aware of at least 40 or 50 cases of ONJ nationwide in patients who had taken Fosamax.That's a infinitely small fraction of the approximately 3 million women in the USA who are taking the drug, although most experts agree that only 1% to 10% of adverse events linked to drugs are reported

While all forms of bisphosphonates, both oral and injectable, may increase the risk of bis-phossy jaw, it is the injectable medications, that appear to pose the greatest risk, according to John
W. Hellstein, DDS, MS

3/05 USA Today

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Treatment:

Ozone

Biophosphonates Warning

Expert Panel Recommendation for the Prevention, Diagnosis and Treatment of Osteonecrosis of the Jaw.

Zometa (zoledronic acid), Aredia (pamidronate disodium) - Labeling  revised to describe the occurence of osteonecrosis of the jaw (ONJ)  observed in cancer patients receiving treatment with intravenous bisphosphonates. USA FDA (Posted 05/18/2005)

http://www.fda.gov/medwatch/SAFETY/2005/zometa_deardentite_5-5-05.pdf

Resources:

Purcell PM, Boyd IW. Bisphosphonates and osteonecrosis of the jaw.
Medical Journal of Australia  2005 Apr 18;182(8):417-8.
PMID: 15850440 [PubMed - in process]
Free Full Text
http://www.mja.com.au/public/issues/182_08_180405/pur10144_fm.html

Carter G, Goss AN, Doecke C. Related Articles, Links Bisphosphonates and avascular necrosis of the jaw: a possible association.
Med J Aust. 2005 Apr 18;182(8):413-5. No abstract available.
PMID: 15850439 [PubMed - in process
Free Full Text
http://www.mja.com.au/public/issues/182_08_180405/car10429_fm.html

Melo MD, Obeid G. Osteonecrosis of the maxilla in a patient with a history of bisphosphonate therapy.
J Can Dent Assoc. 2005 Feb;71(2):111-3
Free Full Text
http://www.cda-adc.ca/jcda/vol-71/issue-2/111.pdf

Robinson NA, Yeo JF. Bisphosphonates--a word of caution.
Ann Acad Med Singapore. 2004 Jul;33(4 Suppl):48-9. Review.
PMID: 15389307 [PubMed - indexed for MEDLINE]
Free Full Text
http://www.annals.edu.sg/pdf200409/V33N4p48S.pdf

Hellstein JW, Marek CL. Bisphosphonate osteochemonecrosis (bis-phossy jaw): is this phossy jaw of the 21st century?
J Oral Maxillofac Surg. 2005 May;63(5):682-9.
http://www2.joms.org/scripts/om.dll/serve?action=searchDB&searchDBfor=art&artType=abs&id=as0278239105001011&nav=abs

ADA Informed Consent

Penn AGD Informed Consent
 

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March 21, 2008

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