Bisphosphonate medications and Osteonecrosis of the jaw

Bisphosphonate medications and Osteonecrosis of the jaw

By Namou Kim, MD, FACS
Medical Director, Swedish Head & Neck and Reconstructive Surgery

Bisphosphonate use has been increasing in recent years.  This is a class of medications that is used to solidify bone mass and prevent fractures.  They fight osteoporosis, but also prevent many cancers from spreading into skeletal bones (bone metastases).  Many patients with metastatic cancers (breast, prostate, renal cell, multiple myeloma, etc.) will require these medications to counteract the devastating consequences of bone metastases.

Bisphosphonates were described as early as the 19th century, and were approved by the FDA in the 1990s for human use.  Fosamax was the first FDA approved bisphosphonate in the USA.   The medications come in an oral (pill) form and an IV version.  Other commonly prescribed bisphosphonates include:

  1. Zometa  (Zolendronate)
  2. Actonel  (Risedronate)
  3. Boniva  (Ibandronate)
  4. Aredia  (Pamidronate)

An uncommon but significant potential side effect of bisphosphonates is the development of Bisphosphonate-associated Osteonecrosis of the Jaw (BONJ).  This is primarily associated with the IV form of the medication. This is a situation in which the jaw bone will essentially become non-viable, resulting in “dead” bone.  While the process is not completely understood, we do know that the cells that start the bone remodeling process are impaired indefinitely which can prevent normal healing.  We also know that the half-life of bisphosphonates is measured in years, so merely quitting the medication once a patient starts developing BONJ will not be enough to stop it from evolving further.  Osteonecrosis has been known to occur spontaneously in up to 4% of patients receiving bisphosphonate therapy, with the IV infusion causing more problems than the pill form.

Symptoms range from jaw bone protruding through the lining of the oral cavity, chronic infections into the outer skin, pain, and even fracture of the jaw.  For early stage BONJ, local debridement of the non-viable bone can be effective, along with meticulous oral hygiene.

When BONJ progresses to full necrosis of an entire segment of the jaw, often times the only meaningful course of action is to resect or remove the dead portion of the jaw.  This has to be done concurrently with reconstruction utilizing a bone from the leg or shoulder blade.  This is a very large surgical undertaking, with a fairly long recovery period.  In these situations the patient rarely returns to normal function or appearance.

Although the risk of developing BONJ is relatively low, the effects can clearly impair the quality of one’s life.  Because the jaw bone can no longer heal normally, dental extractions, periodontal therapy and implants are contraindicated after IV Bisphosphonate use.  Patients, especially those with poor oral hygiene, often endure chronic pain and dental abscesses that can only safely be treated with root canals which are more expensive and time-consuming than extractions. 


Panorex of a right-sided BONJ in a patient with metastatic renal cell carcinoma on Zometa

Obviously, the best therapy is prevention.  It is imperative that patients considering using bisphosphonates see their dentist to get dental clearance before taking the medications.  All non-salvageable teeth should be extracted and dental caries and/or periodontal diseases should be taken care of before the start of bisphosphonates.  One of the main inciting risks of severe BONJ has been shown to be dental extractions during or after therapy with bisphosphonates. 

Dr. Amy Winston, Director of Dentistry at Swedish, emphasizes this, “If we can meet patients prior to starting the medications and get all of their dental needs addressed, the patient has a much lower risk for developing BONJ.  We have seen some very severe cases where the dentistry was not taken care of early and went on to create some very debilitating and challenging situations to handle.  Early exam, early intervention, all prior to bisphosphonates is ideal.  Once the bisphosphonates have started, the next best thing is to have excellent oral care both at home and with a dentist that understands how to manage patients using these medications.”

Comments
Christopher Shuhart, MD
I was informed that this post had been tagged to the Swedish Bone Health web page, and after reviewing it I felt it important to point out some additional facts regarding bisphosphonate (BIS) use for fracture risk and medication-related osteonecriosis of the jaw (MRONJ)

1) this phenomenon is rightly called MRONJ since it is now clear that other non-bisphosphonate cancer treatments are associated with risk. BIS have become synonymous with MRONJ, and are unfairly singled out.

2) BIS use in osteoporosis (based on prescriptions filled and retail sales - including intravenous therapy) has actually declined in the US by 20-50% since 2008 - despite increasing incidence of osteoporotic fractures as the US elderly population grows (Bone. 2013 Dec;57(2):423-8.). Although the factors in the decline are not clear, postulates include negative publicity about BIS. Less treatment means more fractures, pure and simple.

3) Most recent revision of opinions from the American Association of Oral Maxillofacial Surgeons (AAOMS: http://www.aaoms.org/members/resources/aaoms-advocacy-and-position-statements/) in 2014 states :

a) probable risk of ONJ in cancer patients (treated with cancer doses of IV BIS) is 1 %, not 4%, from best clinical trials and systematic review data

b) estimates of risk of ONJ in osteoporosis (OP) patients treated with oral BIS range from 1/500 patients (one study, patients treated for average 4+ years) to 1/100 K patients (one large registry, not a clinical trial), with most centered around 1/1K to 1/10K - meaning we'd have to look at around 1000 to 10000 patients at any one point in time on oral BIS for OP to find one with ONJ.

c) the risk of ONJ associated with injected BIS in OP is indistinguishable from the risk in the placebo arms of the same trials (yes, some patients on placebo get ONJ). The risk is similarly extremely low: 1.7 - 4 patients per 10 K patients treated for three years, with no increasing frequency after six years of treatment in the two treatments (zolendronic acid and denosumab) rigorously studied.

Patient-related (as opposed to medication-related) factors have a majority role to play in MRONJ: cancer status, oral status, oral surgical procedures involving bone, smoking, diabetes, and nutritional status. Given present prevalence of BIS use, rates of MRONJ would be much higher if medications were solely the cause.

Per the AAOMS 2014 Positions, randomized trials show patients who are contemplating treatment for OP with bisphosphonates benefit from working with a dental provider on preventive dental measures before bisphosphonate treatment starts. They should be evaluated prior to initiation and a joint plan created. Treatment of important dental problems should not be delayed for those on BIS. Serum bone metabolism tests are no longer endorsed, and the "drug holiday" approach recommendation has been modified. MRONJ is treatable and in the vast majority of cases resolves without major surgery of any kind.

It is important to remember that there is risk in *not* treating OP : the risk of fragility fracture that causes thousands of excess deaths in the US every year and $20 B in health care costs. (www.nof.org) In general, reatment lowers that risk by half. This risk of MRONJ on treatment is 100-1000 times less likely than the risk of osteoporotic fracture with out treatment, should the patient choose to avoid treatment because of medication risk. This is the burden of suffering of the disease that most of us have no contact with until it's too late. This risk of fracture without treatment is lost in the whirl of emotions evoked by the notion of a "bad medicine". It's the fractures that we should be most concerned about, not the treatments.
3/29/2014 12:32:16 PM
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About the Author

Namou Kim, MD, FACS

Namou Kim, MD, FACS
Medical Director, Swedish Head & Neck and Reconstructive Surgery

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