Osteonecrosis


Clinical Background

Bisphosphonates (also called diphosphonates) are members of a class of drugs that inhibit osteoclast action and the resorption of bone used in the prevention and treatment of osteoporosis, osteitis deformans (“Paget’s disease of bone”), bone metastasis (with or without hypercalcemia), multiple myeloma and other conditions that feature bone fragility. Following initial reports in 2002, osteonecrosis of the jaw (ONJ) has evolved into a recognized adverse event associated with infused bisphosphonates (nitrogen containing) in the oncology population. While the precise incidence of the condition remains to be defined, a recent report places it at ~8%. There is currently no predictable treatment for ONJ. Since bisphosphonates are also used to treat osteoporosis, it is possible that additional patient populations may be at risk for ONJ.

Preclinical Models

Model Description Length Endpoints
Osteonecrosis of the Jaw (ONJ)
Rats are treated with zoledronic acid and dexamethasone prior to dental extractions resulting in ONJ like changes Up to 49 days Osteonecrosis score, x-ray densitometry, histology

 

Osteonecrosis of the Jaw (ONJ)

Studies of the natural history, pathogenesis, and risk determination have been limited by the need for human material and the absence of clinical predictability. In an effort to overcome this constraint, we initiated studies to develop an animal model that mimicked the clinical condition. In proof of concept studies, we were able to induce ONJ in rats following a course of dental extractions coupled with zoledronate and dexamethasone. ONJ is evaluated by direct observation of the wound site, X-ray densitometry to evaluated bone density, routine histology and specific analysis of markers like TRAP.

Normal Jaw

Bronj Jaw

 

Representative histologic sections to illustrate features of intact and ulcerated mucosa. Histologic appearance (4X) of a specimen from a control animal sacrificed 28 days after the extraction of maxillary molars demonstrating intact epithelium overlying an inflammatory infiltrate and healing bone (Panel A). Panel B demonstrates ulceration overlying bony sequestra and marked inflammation. The specimen was taken for an animal treated with ZA/DX and obtained 28 days following extraction (4X). Sequestra of necrotic bone were apparent in areas of ulceration, typically surrounded by an inflammatory infiltrate (Panel C). In comparison, healing bone, unaffected by necrosis, is apparent in panel D with easily viewed osteoid deposition (10X).

 

Publications

Bony changes in the jaws of rats treated with zoledronic acid and dexamethasone before dental extractions mimic bisphosphonate-related osteonecrosis in cancer patients
Sonis ST, Watkins BA, Lyng GD, Lerman MA, Anderson KC
Oral Oncology PMID: 18715819