Scientists are closing in on the solution to an old medical mystery: why do high doses of cortisone, which are widely prescribed for asthma, rheumatoid arthritis and other inflammatory and autoimmune conditions, weaken bones?

"High-dose cortisone is the second most common cause of osteoporosis, and we currently have no real treatment for this serious side effect," says Steven L. Teitelbaum, M.D., Messing Professor of Pathology and Immunology at St. Louis's Washington University, "Given how frequently these drugs are used to treat many different conditions, that's a major clinical problem."

Through studies of mice, Teitelbaum and other researchers have identified osteoclasts, cells that continually dismantle the body's old bone so that it can be replaced by new bone, as the essential link between osteoporosis and cortisone. They published their results in the August 2006 issue of the Journal of Clinical Investigation.

Cortisone is a steroid produced naturally by the adrenal gland and synthesized by pharmaceutical companies. It is used to treat lupus, multiple sclerosis, emphysema and is prescribed to transplant patients to prevent rejection of transplanted organs.

Earlier attempts to identify the connection between bone loss and cortisone had produced contradictory results.

Teitelbaum was struck by a new way to investigate the connection while listening to a lecture by Washington University colleague Louis J. Muglia, M.D., Ph.D., director of pediatric endocrinology at St. Louis Children's Hospital. Muglia studies the health effects of stress, many of which are mediated by cortisone. To aid his research, Muglia developed a line of genetically modified mice where receptors for cortisone could be selectively eliminated in individual cell types.

By crossbreeding genetically modified mouse lines, researchers produced a line of mice whose bone-dismantling osteoclasts lacked cortisone receptors. When researchers gave cortisone to these mice, the bone-weakening effects of the drugs were blocked.

They also found that cortisone blocks osteoclasts from dismantling old bone in genetically normal mice. This causes the regular skeletal renewal process to stop, in turn causing bones to weaken from aging and stress. Dampening osteoclast activity appears to cause a chain reaction that actually slows bone-building.