Research Seeks to Stop Bone Loss in Rheumatoid Arthritis Patients

Rosalind Russell Center donors help support promising basic science initiative

Dr. Mary Nakamura is conducting pioneering research on one of the most serious consequences of rheumatoid arthritis (RA): bone loss, which can make daily activities difficult and lead to the need for joint replacements. A distinguished laboratory scientist and associate professor in the UCSF Division of Rheumatology, Dr. Nakamura hopes her findings will eventually contribute to better detection and treatment of bone loss in patients with RA and other inflammatory autoimmune diseases.

"While healthy bone seems like a static organ, about 10 percent of the human skeleton is replaced every year," says Dr. Nakamura. This occurs through the precisely equivalent dual processes of bone degradation and formation, each performed by a different type of cell. "In rheumatoid arthritis, however, the balance between the function of those two cells becomes disregulated and bone loss wins out."

Dr. Nakamura is the recipient of two highly prestigious awards: the Presidential Early Career Award from the National Institutes of Health, and the Henry Kunkel Young Investigator Award from the American College of Rheumatology. She is a graduate of the UCSF Rheumatology Fellowship Program, a three-year training for physicians to become rheumatologists and arthritis investigators. Her fellowship was partially funded by the Rosalind Russell Medical Research Center for Arthritis.

Rheumatoid arthritis patients can experience two very different kinds of bone loss. Parts of bone can actually be eaten away in specific inflamed joints, making the joints abnormal and less functional. Alternatively, extensive inflammation throughout the bodies of RA patients can cause generalized loss of bone density, very similar to what happens in postmenopausal osteoporosis. As in postmenopausal osteoporosis, this results in fragile bones that are more susceptible to fracture.

Both kinds of bone loss are caused by excessive activity of the cells responsible for bone degradation in the ongoing process of bone replacement. Why do these cells, called osteoclasts, go into overdrive? According to Dr. Nakamura, inflammation changes the environment in which these cells develop, and triggers greater production and over-activity of these cells.

Several small studies suggest that the frequently-prescribed RA drug methotrexate, which controls inflammation, also prevents bone erosion in about two-thirds of the patients for whom it is effective in relieving symptoms. But it is not possible to predict during treatment which patients respond with decreased inflammation but have ongoing bone erosion. Among RA patients taking the new class of drugs called TNF inhibitors, there is significant reduction of inflammation and bone erosion.

"We currently do not have clear methods to detect ongoing bone erosion," says Dr. Nakamura. "We measure it retrospectively after damage occurs by visualizing it on x-rays. We are working to determine if analysis of osteoclasts and osteoclast precursors can help us in this regard. We want to understand more specifically how inflammation regulates the subsequent development of osteoclasts. If we can find out how to decrease the number and/or the activity of osteoclasts, then perhaps we would be able to block bone loss during inflammation, but leave normal bone turnover alone. That is the eventual goal. "

To date, Dr. Nakamura has been working with cells from a mouse model for RA to better understand under what circumstances the osteoclasts are activated. In the coming year or so, she will begin working with human cells. This big step forward into what is called translational research could lead to a tool to predict which patients are at highest risk for progressive bone loss. "It is our hope that such early identification can facilitate treatment decisions that may prevent problems due to bone loss in patients with inflammatory arthritis," she says.

(Published June 2008 in Arthritis Progress Report, the newsletter of the Rosalind Russell Medical Research Center for Arthritis. To be added to our mailing list, please send us a note with your name and address to Your information will not be shared with any other organizations.)

"We want to understand how inflammation changes the environment in which these cells develop."

-- Dr. Mary Nakamura

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