Researchers Show COX-2 Inhibitors Interfere With Bone Growth, Healing

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Source: Stanford University Medical Center

Date:

11/20/2002

Researchers Show COX-2 Inhibitors Interfere With Bone Growth, Healing

STANFORD, Calif. - Researchers at Stanford University Medical Center have

found that selective COX-2 inhibitors - a class of medications widely

prescribed for painful inflammatory conditions such as osteoarthritis and

rheumatoid arthritis - interfere with the healing process after a bone

fracture or cementless joint implant surgery. Their findings, published in

the November issue of the Journal of Orthopaedic Research, suggest that

patients who regularly take COX-2 inhibitors should switch to a different

medication, such as acetaminophen or codeine derivatives, following a bone

fracture or cementless implant. The study, conducted in rabbits, also

suggests that physicians should consider changing prescribing patterns since

many doctors commonly prescribe anti-inflammatory drugs including COX-2

inhibitors under the very circumstances in which the drugs should be

avoided.

" It's very common. You break a bone and go to the ER. The doctor sets it in

a splint and prescribes one of these anti-inflammatory drugs (including

COX-2 inhibitors) for pain, " said Stuart Goodman, MD, professor of

orthopaedic surgery at the Stanford School of Medicine and lead author of

the study. " We now know that could actually delay healing. "

The enzyme Cyclooxygenase-2, or COX-2, is produced by the body in response

to injury or inflammation. COX-2 inhibitors, including anti-inflammatory

medications such as rofecoxib (Vioxx), celecoxib (Celebrex) and others,

block production of this enzyme. Goodman's research shows that COX-2

inhibitors also impede the new bone growth that normally helps heal a

fracture or stabilize a joint implant.

Belonging to a class of medications called non-steroidal anti-inflammatory

drugs, COX-2 inhibitors were developed in the late 1990s as an alternative

to another group of medications called nonspecific NSAIDS, which inhibit the

production of COX-2 along with the enzyme Cyclooxygenase-1, or COX-1.

Nonspecific NSAIDS, including aspirin, ibuprofen, naproxen and others, often

cause stomach irritation and a tendency to bruise easily. COX-2 inhibitors

largely avoid these side effects.

Researchers confirmed years ago that nonspecific NSAIDS inhibited bone

growth and healing, but the Stanford study is among the first to show that

COX-2 inhibitors have the same effect.

In the tibia bone of eight New Zealand white rabbits, Goodman and his team

implanted a titanium device called a harvest chamber, which resembles a

small screw. The device has a removable, hollow inner core that allows

researchers to periodically extract the tissue growing inside. The growth of

new bone into the chamber simulates healing of a fracture or joint implant.

Researchers gave the rabbits the following oral treatments for four weeks

each: plain water; water with naproxen; plain water again; and sugar-coated

pellets of rofecoxib (a COX-2 inhibitor). After each treatment, researchers

removed the harvest chamber's core and extracted the tissue growing inside.

After preserving the tissue in liquid nitrogen, the researchers sectioned

and processed it with special stains including monoclonal antibodies,

allowing them to see how new bone had grown back.

Because a harvest chamber allows new tissue to be extracted multiple times

as it grows back, the rabbits served as their own control groups (after

consuming plain water) as well as the two experimental groups (after

consuming naproxen and rofecoxib). The researchers found that while the

tissue in the control group contained 24.8 percent and 29.9 percent new bone

growth, the tissue harvested after the rabbits consumed naproxen and

rofecoxib contained significantly less - 15.9 percent and 18.5 percent

respectively. The difference in new bone growth associated with the two

drugs was statistically insignificant; practically speaking, the COX-2

inhibitor impeded new bone growth as much as the nonspecific NSAID.

While acknowledging the limitations of animal research, Goodman said this

study " has great applicability to humans, because the healing process is

virtually the same " for rabbit and human bones. Goodman is having his own

patients avoid COX-2 inhibitors for six weeks after a fracture or joint

implant, and he recommends other physicians do the same. " This research has

very practical applications. "

Goodman said his recommended six-week " time-out " period is an educated

guess, because his study didn't address how long the bone-growth-suppressing

effects of COX-2 inhibitors last. To answer that question, Goodman and his

colleagues recently began a follow-up study.

Stanford University Medical Center integrates research, medical education

and patient care at its three institutions - Stanford University School of

Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital

at Stanford. For more information, please visit the Web site of the medical

center's Office of Communication & Public Affairs at

http://mednews.stanford.edu.