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Pathophysiology and Clinical Studies of Osteonecrosis of the Jaw (ONJ)

Clinical Trials Program, Center for Clinical Research
Division of Extramural Research

Reports regarding bisphosphonate-associated osteonecrosis of the jaw (ONJ) have focused on the clinical presentation of this oral condition and its estimated prevalence in selected populations. Published management recommendations are based on anecdotal reports or expert opinion.  The underlying pathophysiology remains largely unexplored, and there are no evidence-based treatments for patients.  This research initiative would address gaps in our understanding of how bisphosphonates may interfere with oral mucosal healing and bone repair at the genetic, molecular, cellular, and tissue levels.  This initiative would also address the need for studies to identify risk factors for this condition, establish the natural history of the disease, and generate preliminary evidence for its treatment.  This information could present new opportunities for designing prevention and intervention strategies for ONJ, and for investigating ONJ associated with other new anti-resorptive drugs.  The combined solicitation of patho-physiological and clinical studies underscores the need for translational research on this topic.


The bisphosphonates are a class of drugs that inhibit the activities and functions of osteoclasts (bone resorbing cells) and perturb the differentiation of osteoblasts (bone forming cells). Intravenous bisphosphonates are used primarily to treat the pain, bone resorption and hypercalcemia associated with cancer metastasis and multiple myeloma. Oral bisphosphonates are used to prevent bone loss and are prescribed for patients with osteoporosis, osteopenia and Paget’s disease.  In 2003, reports appeared in the literature that suggested an association of ONJ with bisphosphonate use in a subset of patients. Patients with ONJ present with painful, exposed necrotic bone of the maxilla or mandible.  These slow or non-healing lesions often develop following invasive dental procedures, but they may develop spontaneously.  Secondary infection of the necrotic bone can result in a localized osteomyelitis.  Various reports have estimated the incidence and prevalence of this condition, but the range is large and the estimates need to be verified.  Most cases are related to intravenous bisphosphonate use in cancer patients, but many cases are reported in those using oral bisphosphonates to prevent or treat osteoporosis.  Currently, there are no evidence-based treatments for ONJ.  Patients may be treated non-invasively with antibiotics and chlorhexidine mouth rinses to prevent secondary infection. Surgical interventions such as local debridement or resection of necrotic bone have not been evaluated for their effectiveness.  Taking “drug holidays” is an option to be explored and should only be approached with caution to balance the benefits and risks of bisphosphonate use.  While ONJ affects relatively few patients taking oral bisphosphonates, the oral forms are used long term by millions of patients world-wide.  Very recent data suggest newer biological agents that inhibit osteoclast-mediated bone resorption may be associated with ONJ.  Therefore, ONJ research has the potential to have broad health impact.

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This page last updated: February 26, 2014