ScienceDaily (Jan. 27, 2012) — New
York, NY (January 26, 2012) — 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.

Oral bisphosphonates are currently taken by some 3 million
women in the United States for the prevention or treatment of
osteoporosis. In addition, intravenous bisphosphonates are
given to thousands of cancer patients each year to control the
spread of bone cancer and prevent excess calcium
(hypercalcemia) from accumulating in the blood. Bisphosphonates
work by binding to calcium in the bone and inhibiting
osteoclasts, bone cells that break down the bone’s mineral
structure.

“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.”

Osteonecrosis of the jaw, or ONJ, often leads to painful and
hard-to-treat bone lesions, which can eventually lead to loss
of the entire jaw. Among people taking bisphosphonates, ONJ
tends to occur in those with dental disease or those who
undergo invasive dental procedures.

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 percent 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.”

The current study looked only at Caucasians. Further studies
are needed to determine whether the RBMS3 gene variation is
seen in other racial groups, according to the researchers.

The paper is entitled, “Genome-wide pharmacogenetics of
bisphosphonate-induced osteonecrosis of the jaw: the role of
RBMS3.” The lead authors are Paola Nicoletti of CUMC and
Vassiliki M. Cartsos of Tufts School of Dental Medicine. The
other contributors are Penelope K. Palaska of Tufts and Yufeng
Shen and Aris Floratos at the Columbia University Medical
Center Bioinformatics Department.

This research was supported by grant number 7R21DE018143-03
from the National Institute of Dental and Craniofacial
Research.
Columbia University has filed a patent application with the
United States Patent and Trademark Office relating to a genetic
screening test for predisposition to ONJ, and, through its
technology transfer office, Columbia Technology Ventures, is
actively seeking partners to collaborate, license and
commercialize the technology.
-####-

Columbia University College of Dental Medicine (CDM) was
established in 1916 as the School of Dental and Oral Surgery,
when the School became incorporated into Columbia University.
The College’s mission has evolved into a tripartite commitment
to education, patient care, and research. The mission of the
College of Dental Medicine is totrain general dentists, dental
specialists, and dental assistants in a setting that emphasizes
comprehensive dental care delivery and stimulates professional
growth; inspire, support, and promote faculty, pre- and
postdoctoral student, and hospital resident participation in
research to advance the professional knowledge base; and
provide comprehensive dental care for the underserved community
of northern Manhattan. For more information, please visit:
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Columbia University Medical Center provides international
leadership in basic, pre-clinical and clinical research, in
medical and health sciences education, and in patient care. The
medical center trains future leaders and includes the dedicated
work of many physicians, scientists, public health
professionals, dentists, and nurses at the College of
Physicians and Surgeons, the Mailman School of Public Health,
the College of Dental Medicine, the School of Nursing, the
biomedical departments of the Graduate School of Arts and
Sciences, and allied research centers and institutions.
Established in 1767, Columbia's College of Physicians and
Surgeons was the first institution in the country to grant the
M.D. degree and is among the most selective medical schools in
the country. Columbia University Medical Center is home to the
largest medical research enterprise in New York City and State
and one of the largest in the United States.

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