For thousands of transplant patients in the United States, glucocorticoids--a class of steroidal immunosuppressive medications--are a life-sustaining commodity: the drugs keep their bodies from rejecting the newly transplanted organs. Thousands more patients also use these drugs to deal with such chronic diseases as rheumatoid arthritis, lupus and asthma.
But despite their apparent success, glucocorticoids have a substantial shortcoming: long-term users often develop osteoporosis, a condition of serious bone weakening and loss that puts the body at risk for fractures and subsequent disability. Osteoporosis is a major threat for 28 million Americans and the cause of 1.5 million fractures and an estimated $13.8 billion in health care costs annually. Steroid-induced osteoporosis is but one variation of osteoporosis.
Scientists at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and at other institutions around the country have long been interested in learning the mechanism behind glucocorticoid-induced bone loss, reasoning that the mechanism held the key to improved treatment and prevention of this loss. Investigators have tried to study the effects of glucocorticoids on bone cells grown in culture, but isolating these effects has proven difficult. In a real skeleton, bone is constantly being broken down and replaced, and osteoblasts and osteoclasts (cells that build up and break down bone cells) are themselves continuously dying and being replaced by new cells from the bone marrow.
Researchers have also looked for an animal model to reproduce the glucocorticoid effects they saw in human patients. Tests in rats and rabbits, however, failed.
Recently, investigators at the University of Arkansas for Medical Sciences, with support from NIAMS and the National Institute on Aging, have used a mouse model and cell culture techniques not only to shed new light on glucocorticoids' destructive mechanism, but to point the way to preventive measures. The team of scientists, led by Stavros Manolagas, M.D., Ph.D., has been able to show that mice treated with prednisolone, a commonly used glucocorticoid, have bone loss similar to that seen in human patients (J Clin Invest 1998;102:274-282). The research team also found that:
- the prednisolone-treated mice had reduced numbers of bone-forming osteoblasts.
- glucocorticoid reduced the rate of osteoblast formation in cell cultures of mouse bone-marrow cells.
- a greater number of dying bone cells were present in prednisolone-treated mice than in untreated mice.
The University of Arkansas group discovered that the dying bone cells included not only osteoblasts, which are present on bone surfaces, but osteocytes, which are imbedded in the bone itself and are thought to help stimulate bone formation. This finding paralleled an increase in dying osteoblasts and osteocytes in patients with glucocorticoid-induced bone loss.
The Arkansas study shows that glucocorticoids may both reduce the formation of new bone cells and increase the death of cells important to new bone cell development. But how could knowing these mechanisms help prevention efforts?
The process of programmed cell death, also called apoptosis, occurs at increased rates in bone cells during glucocorticoid treatment. The process is a highly controlled one that is usually triggered by a specific signal. If glucocorticoids act as a signal to osteoblasts and osteocytes to begin the dying process, and if the nature of that signal can be determined, it may be possible to design drugs to block the signal and spare many bone cells that might otherwise be lost.
For thousands of transplant patients, arthritis and asthma sufferers, and others at risk for steroid-induced bone loss, that's good news.
The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the National Institutes of Health (NIH), leads the Federal medical research effort in arthritis and musculoskeletal and skin diseases. The NIAMS supports research and research training throughout the United States, as well as on the NIH campus in Bethesda, MD, and disseminates health and research information. The National Arthritis and Musculoskeletal and Skin Diseases Information Clearinghouse (NAMSIC) is a public service sponsored by the NIAMS that provides health information and information sources. Additional information can be found on the NIAMS Web site at http://www.niams.nih.gov/.