(Drug Induced Osteonecrosis of the Jaws)

In 2003, oral and maxillofacial surgeons began to see a growing number of patients with painful, exposed dead or dying bone in the jaws (osteonecrosis). Investigation of this problem revealed a link between these cases and use of bisphosphonate drugs. Other Drugs now known to cause this are Denosumab drugs (Xgeva and Prolia). Bisphosphonate drugs are a class of drugs used to prevent loss of bone mass. High potency intravenous bisphosphonates have been shown to reduce skeletal complications and progression of malignant bone disease in several forms of cancer, especially breast and prostate cancer. Oral Bisphosphonates are used to treat osteoporosis, osteopenia and other conditions leading to bone fragility (i.e. osteitis deformans or Pagets disease of bone). Denosumab drugs are used for cancer treatment as well as for osteoporosis. Bisphosphonate drugs bind tightly to the bone. These drugs prevent osteoclasts (cells responsible for active dissolving of bone during bone remodeling), from doing their job. As a result, bone production continues, bone loss decreases, bone density is improved and the risk of fracture reduced. Denosumab drugs prevent formation and affect precursor cells of osteoclasts.

Due to their affinity for bone, these  drugs can irreversibly cause an alteration in bone healing. This presents a risk when doing oral & maxillofacial surgery. Even minor oral surgery (i.e. taking out a tooth), can result (rarely) in long-term exposed or non-healing bone. This exposed bone may be painful and can rarely result in a pathologic fracture of the lower jaw. The clinical scenario of someone who has taken these medications and has exposed bone that doesn’t heal is called drug induced osteonecrosis of the jaws, or DIONJ. Some patients taking these drugs have no exposed bone while other patients have significant exposed bone, morbidity and pain.

Some of the bisphosphonates of drugs include: Fosamax , Actonel, Boniva, Zometa, Reclast, Aredia

Some of the denosumab drugs are: Xgeva ( for cancer treatment) and Prolia (for osteoporosis).

Other drugs implicated in DIONJ are : Avastin ( Bevacizumab) and Sutent( Sunitinib)

Patients may be considered to have DIONJ  if all of the following three characteristics are present:

  1. Current or previous treatment with a bisphosphonate or denosumab drug.
  2. Exposed, necrotic bone in the maxillofacial region that has persisted for more than eight weeks
  3. No history of radiation therapy to the jaws.

The following are thought to be risk factors for developing BRONJ:

  1. Corticosteroid therapy
  2. Duration of bisphosphonate/denosumab treatment
  3. Tooth extraction/osseous periodontal surgery/dental implant placement
  4. Diabetes
  5. Smoking
  6. Alcohol use
  7. Poor oral hygiene, pre-existing dental or periodontal disease
  8. Chemotherapeutic drugs

The signs and symptoms of DIONJ include: exposed bone; localized pain, swelling and inflammation of gum tissues; loosening of previously stable teeth. The dentist or physician may see radiographic signs if proper studies are taken.

The incidence of DIONJ varies with type of bisphosphonate drug taken (Intravenous vs. Oral), length of time having taken the bisphosphonate drug and disease being treated. The incidence of BRONJ in patients receiving IV bisphosphonates for reduction of skeletal-related complications from bone metastasis of a cancer are 4-18%. The incidence of DIONJ in patients being treated for Osteoporosis or Osteopenia with oral bisphosphonates is in the range of 0.7%-4.8% .

DIONJ can occur spontaneously in patients having taken these drugs. Your dentist or dental specialist should perform an examination immediately if any problem occurs in the oral cavity if you, or a family member, has taken this class of medications. Preventative measures, once exposed to bisphosphonates, include proper dental care by patient and possible consideration for discontinuation of oral bisphosphonate therapy prior to dental treatment if possible. A comprehensive dental exam should be done prior to starting bisphosphonate therapy and patients on bisphosphonates should be encouraged to perform proper mouth care, and receive routine dental examinations.

DIONJ Staging and Treatment (From University of Miami Position Paper-R. Marx et. al)

Stage 0 

Clinical or radiographic evidence of drug toxicity of the jaws. We may see sclerosis of Lamina Dura or widening of PDL on dental radiographs; tooth mobility; pain not explained by obvious dental source. No apparent exposed or necrotic bone is seen. Treat symptoms with NSAID medications, check Occlusion, and possibly use night guard if grinding or bruxism is present.

Stage 1

These patients have exposed/necrotic bone in one quadrant.

Stage 2

These patients have exposed/necrotic bone in two quadrants.

Stage 3

These patients have exposed/necrotic bone in three or four quadrants;pathologic fracture of the jaw; or extension into maxillary sinus.

Treatment: These patients benefit from the use of oral antimicrobial rinses, such as Chlorhexidine 0.12%, in combination with antibiotic therapy. DIONJ is not due to an infectious etiology or cause. Most of the isolated microbes have been sensitive to the pencillin group of antibiotics. Penicillin and doxycycline have been used with success in this group of patients.   In some refractory cases, patients may require  Flagyl or a combination antibiotic therapy, long-term antibiotic maintenance or a course of intravenous antibiotic therapy

Regardless of the disease stage, mobile segments of bony sequestrum should be removed without exposing uninvolved bone. 

Discontinuation of Bisphosphonate Therapy/IV Bisphosphonates

Oncology patients benefit greatly from the therapeutic effects of bisphosphonates by controlling bone pain and incidence of pathologic fractures. Discontinuation of IV bisphosphonates or denosumab treatment offers no short-term benefit. However, if the systemic conditions permit, long-term discontinuation may be beneficial in stabilizing established sites of DIONJ, reducing the risk of new site development and reducing clinical symptoms. The risks and benefits of discontinuing bisphosphonate or denosumab therapy should be made only by the treating oncologist in consultation with the oral and maxillofacial surgeon and the patient.

Discontinuation of Bisphosphonate Therapy/Oral Bisphosphonates

Discontinuation of oral bisphosphonate therapy in patients with DIONJ has been associated with gradual improvement in the clinical disease. Discontinuation of oral bisphosphonates for 9 months may result in spontaneous sequestration or resolution following debridement surgery. If systemic conditions permit, modification or cessation of oral bisphosphonate therapy should be done in consultation with the treating physician and the patient. 

CTX- A Marker for Bone Turnover

There is a blood test available for use as a marker for patients on Oral or IV bishphosphonates or denosumab drugs. This is a fasting blood assay that helps determine collagen turnover, which is an indicator of bone turnover. This may give us a safety valve or some degree of confidence in doing surgery on patient receiving bisphosphonates or denosumab drugs. CTX values are unpredictable in patients with cancer; those taking steroids; or those patients on methotrexate.

CTX values less that 100pg/ml indicate high risk for developing BRONJ with any surgical intervention.

CTX values of 100-150 pg/ml indicate moderate risk for developing BRONJ with any surgical intervention

CTX values of greater than 150 pg/ml indicate minimal or no risk for developing BRONJ with any surgical intervention.

Many experts in this field suggest that if a patient has been on oral bisphosphonates for less than 3 years, most procedures should be safe from developing DIONJ. If taking oral bisphosphonates for more than 3 years, it may be recommended to get a baseline CTX assay. 

If you have an infected tooth or acute problem that requires a NON ELECTIVE surgery, a CTX assay would be academic. If the needed treatment is not done the inflammation or infection may cause bone to become exposed that was otherwise not exposed.

If you are having ELECTIVE oral surgery after having taken a bisphosphonate, it makes good sense to get a baseline CTX assay to assess risk adequately for the procedure.  If this CTX value is less than 150 pg/ml, discontinue oral bisphosphonate with approval of prescribing MD for 9 months:

  • Repeat CTX after 9 month “drug holiday” ( 3 month”drug holiday” for denosumab drugs)
  • Proceed with Dental procedure when CTX is 150 pg/ml or above
  • Restart oral bisphosphonate or denosumab drug 3 months after procedure.