Diagnosis: Osteonecrosis of the jaws by bisphosphonates

DISCUSSION
Bisphosphonates are recently acquiring increasing relevance with regard to the treatment of several pathologies such as lytic bone metastasis, malignant hypercalcemia, multiple myeloma, osteoporosis and Paget’s disease (1,2).

Osteonecrosis of the jaw (ONJ) results from bone exposure in the oral cavity with subsequent necrosis, often following dental procedures or traumatic injuries. Since 2003, there has been increased reporting of ONJ in breast and prostate cancer, and multiple myeloma patients. The main association in all these reports was the use of bisphosphonates (3).

The first large reviews on this complication were published by Marx (4) in 2003 (36 cases), Ruggiero (5) in 2004 (63 cases), and Bagán (6) in 2005 (10 cases).

According to the literature review by Durie et al. (7), the rate of occurrence of ONJ in patients with myeloma or breast cancer treated with high-dose intravenous bisphosphonate therapy for 36 months was 4% with pamidronate (Aredia™) and 10% with zolendronate (Zometa™).
Risk seems to be increased by long-term treatments (longer than one year)(2).
ONJ in patients taking low-dose bisphosphonates to treat non-malignant diseases such as osteoporosis remains exceedingly rare (5).

The mechanisms by which bisphosphonates may cause or promote ONJ remain speculative. One possibility is a decrease in blood supply due to the antiangiogenic properties of bisphosphonates, reducing circulating endothelial growth factor (EGF) (2,5,6).
This relative ischemia of the bone, together with slowing of the bone turnover rate, the underlying disease, chemotherapy, and glucocorticoid therapy may act in conjunction to promote bone infection and necrosis, with tooth extraction being a major risk factor (8). According to Badros et al (3), with each decade of life, there is a 9% increased risk of developing ONJ, and with each passing year of time living with the disease,
there is a 57% increase in the predicted risk of developing ONJ.

The mandible is more often involved than the maxilla. Both sides may be affected. Pain occurring spontaneously and during chewing and tooth brushing is the main symptom, and purulent drainage or extension to a sinus may occur (5).

Clinically, the alveolar ridge is exposed, revealing sequestra of necrotic bone and pus (4,5). Radiographs show decreased bone density in the affected region and patchy sclerosis corresponding to sequestra of necrotic bone, or radiographic images might show a normal structure without visible lesions (2,9).
Histology confirms the presence of infection and necrosis. Cultures recover the saprophytic flora and may reveal infection by Actinomyces (9,10).

There is no consensus on the management of ONJ. Although surgery is potentially curative when performed by experienced surgeons, postoperative complications are significant, and in many cases can result in more bone exposures (3).
Some cases respond to antibiotics. In this sense, penicillins (amoxicillin plus clavulanate) are useful, together with local 0.12% chlorhexidine rinses and debridement (2,4,6).
Abu-Id et al, (10) consider the most effective treatment to be marginal or segmental resection of the jaw.

The best management option comprises careful dental evaluation and preventive care for all patients programmed to receive bisphosphonate therapy (3,8).
According to Brados et al. (3), discontinuation of bisphosphonate therapy has not significantly helped to either reverse the presence of ONJ or ameliorate symptoms of established cases. Whether discontinuing bisphosphonate therapy before elective surgical interventions, such as dental extractions, can prevent the development of ONJ requires further investigations.

References

  1) Heymann D, Ory B, Gouin F, Green JR, Redini F.
      Bisphosphonates: new therapeutic agents for the treatment of bone tumors.
      Trends in Molecular Medicine 2004; 10: 337-43.

  2) Pastor-Zuazaga D, Garatea-Crelgo J, Martino-Gorbea R, Etayo-Pérez A,
      Sebastián-López C.
      Osteonecrosis of the jaws and bisphosphonates. Report of three cases.
      Med Oral Patol Oral Cir Bucal 2006;11:E76-9.

  3) Brados A, Weikel D, Salama A, Goloubeva O, Schneider A, Rapoport A, et al.
      Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors.
      J Clin Oncol 2006;24:945-52.

  4) Marx RE.
      Pamidronate (Aredia) and Zoledronate (Zometa) induced avascualr necrosis of the jaws:
      a growing epidemic.
      J oral Maxillofac Surg 2003; 61:1115-8.

  5) 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.

  6) Bagán JV, MurilloJ, Jiménez Y, Poveda R, Milián MA, Sanchis JM, Silvestre FJ, Scully C.
      Avascular jaw osteonecrosis in association with cancer chemotherapy:
      series of 10 cases.
      J Oral Pathol Med 2005;34:120-3.

  7) Durie BG, Katz M, Crowley J.
      Osteonecrosis of the jaw and bisphosphonates.
      N Engl J Med 2005; 353:99-102.

  8) Naveau A, Naveau B.
      Osteonecrosis of the jaw in patients taking bisphosphonates.
      Joint Bone Spine 2006;73:7-9.

  9) Lugassy G, Shaham R, Nemets A, Ben-Dor D, Nahlieli O.
      Severe osteomyelitis of the jaw in long-term survivors of multiple myeloma: 
      a new clinical entity.
      Am J Med 2004; 117:440-1.

10) Abu-id MH, Acil Y, Gottschalk J, Kreusch T.
      Bisphosphonate-associated osteonecrosis of the jaw.
      Mund Kiefer Gesichtschir 2006;10:73-8.