Bisphossy jaw: is it all in the genes?

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New research suggests a genetic link between the use of oral bisphosphonates, commonly prescribed for osteoporosis, and ONJ.

Researchers at the Columbia University College of Dental Medicine have identified a genetic variation that raises the risk of developing serious necrotic jaw bone lesions in patients who take bisphosphonates, a common class of osteoclastic inhibitors. The discovery paves the way for a genetic screening test to determine who can safely take these drugs. The study appears in the online version of the journal The Oncologist.

The finding is significant because of concerns over recent years that popular treatments for cancer and osteoporosis could result in the return of “phossy jaw”. One of the manufacturers of oral bisphosphonates was recently taken to court by a patient who had developed osteonecrosis of the jaw, or ONJ after dental treatment.

“These drugs have been widely used for years and are generally considered safe and effective,” said study leader Athanasios I. Zavras, DMD, MS, DMSc, associate professor of Dentistry and Epidemiology and Director of the Division of Oral Epidemiology & Biostatistics at the Columbia University College of Dental Medicine. “But the popular literature and blogs are filled with stories of patients on prolonged bisphosphonate therapy who were trying to control osteoporosis or hypercalcemia only to develop osteonecrosis of the jaw.”

There are no reliable figures on the incidence of ONJ in patients taking oral bisphosphonates. Estimates range from 1 in 1,000 to 1 in 100,000 patients for each year of exposure to the medication, according to the American College of Rheumatology. ONJ is more common among cancer patients taking the intravenous form of the drug, affecting about 5 to 10 per cent of these individuals, noted Dr Zavras.

Studies have suggested that genetic factors play a major role in predisposing patients to ONJ. 
Delving deeper into this question, Dr. Zavras and his colleagues performed genome-wide analyses of 30 patients who were taking bisphosphonates and had developed ONJ and compared them with several bisphosphonate users who were disease free.

The researchers found that patients who had a small variation in the RBMS3 gene were 5.8 times more likely to develop ONJ than those without the variation. The study also identified small variations in two other genes, IGFBP7 and ABCC4, that may contribute to ONJ risk.

“Our ultimate goal is to develop a pharmacogenetic test that personalizes risk assessment for ONJ, a test that you could give to people before they start to use bisphosphonates,” said Dr Zavras. “Those who are positive for this genetic variation would select some other treatment, while those who are negative could take these medications with little fear of developing ONJ.”

“At the moment, many women discontinue or avoid treatment for serious osteoporosis because they are afraid of losing their jaw bones,” added Dr Zavras. “There even are reports of dentists who have refused to perform certain invasive procedures in patients taking bisphosphonates. So there is a great need for a pharmacogenetic screening test to determine which patients are really at risk for ONJ.”

 

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