in another request for applications in interventions in the elderly who have osteoporosis.

In the meantime, we have had some research advances in osteoporosis. A key one, as you know, are the bisphosphonates which are used to retard bone loss in post-menopausal women. It provides an alternative to estrogen replacement therapy, which has been confirmed once again as being valuable. We need to find the best type of hormone combinations for that effort.

Calcium is important at all ages. Let me indicate that we have had a very interesting study this year in young twins, children. Some twins have been taking the ordinary amount of calcium that children are supposed to take; their twin pairs have taken a supplement of twice that much. Those who have taken the supplement have built up more dense bones than the others who have taken the ordinary amount.

We have had a study report in the New England Journal of Medicine of women who are not producing the normal amount of hormones during their twenties, thirties, and forties; they have lower bone mass than other women who menstruate normally.

We have also had studies showing that running in the elderly may actually be helpful.

The right amount of exercise is a problem not only for all of us, but especially for our astronauts.

Senator HARKIN. Excuse me. Did you say running?

Dr. SHULMAN. Older people running. It is good for them, good for their bones.

Senator HARKIN. Thank you. Now, I have it clear in my head. It is good for older people to run. All right. [Laughter.]

Dr. SHULMAN. It's good for their bones. This is a problem for our astronauts. If we are going to go to Mars, either with or without the Soviets, we have to be sure that the astronauts don't lose much of their bone mass. So, we are working with NASA on this.

LYME DISEASE

Another area of importance that has interested both you and us is Lyme disease. We appreciate that this disease is still spreading. Last year, as you know, we issued a request for applications on causal mechanisms. With your special emphasis this year, we have responded with another request for applications, this time for research on the diagnosis and treatment of Lyme disease, both of which are still problems. We have keen problems in the diagnosis of Lyme disease. There is difficulty in defining it with great accuracy, and we do not have fully reliable laboratory tests. Various tests do not agree with one another, according to a study done by the CDC and as reported at a conference last fall.

There seems to be both underdiagnosis and overdiagnosis in endemic areas. So, this is another type of problem. And certain outdoor workers, such as forestry workers, are actually at special risk, and we need to have preventive modes for them.

OSTEOARTHRITIS

We have had exceptional discoveries in two areas. The first is osteoarthritis, the most common form of arthritis usually occurring in

the elderly. As you know, our investigators discovered a faulty gene in a particular familial form of osteoarthritis. This arthritis occurred in youngsters. The scientists were able to identify, in a family of three generations in which nine of the members developed severe osteoarthritis in their twenties, this specific fault in the gene for collagen II. Collagen II is a molecule of 1,000 amino acids. They found the fault in a substitution of only one of these amino acids for another. This provides a new direction for research on osteoarthritis generally, and this work is now beginning.

The second spectacular discovery is that of research in using transgenic animals to study the spondyloarthropathies. This is a group of diseases associated with arthritis of the spine and other joints and other manifestations. This is a common disease of young men, perhaps the most common form of arthritis in young men. It had been found that there is a tissue type, HLA-B-27, that was associated with these diseases. It had been suspected that certain infections actually initiate these diseases. There had been some question about the importance of genetics. With this transgenic mechanism, they have been able to take the human B-27 gene, inject it into the fertilized egg of in-bred rats, and then reproduce the whole human disease. This establishes a clear role for genetics in these forms of arthritis. Spectacular.

We also have interesting work going on in lupus. Lupus, as you know, is nine times more common in women, three times more common in black women than white women. We have a whole task force to look into why this is so and what we could do in educating those at special risk.

PREPARED STATEMENT

Finally, we have made giant steps in developing our national research plan. I believe we advised you last year that it was going to take us about 2 years to develop that plan. We are clearly ahead of that schedule. We had a national task force meet in February, north of Baltimore, with 140 of the leading scientists in the Nation, in five different disease areas, Senator Harkin. We had five science panels with anywhere between 22 and 35 leaders each in arthritis, muscle biology, bone biology and bone diseases, musculoskeletal, orthopedic disease, and dermatology; and nine crosscutting issues panels. They have come up with a research plan in draft of about 1,000 pages, with very exciting recommendations for the future. It will take us a few months to complete the final report of the national plan, and we will be glad to submit it to you then.

That is our report, sir.

[The statement follows:]

38-711 0-91-35

STATEMENT OF DR. LAWRENCE D. SHULMAN

The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) supports a broad range of basic and clinical research on many of the most debilitating diseases affecting the health of the Nation. I am privileged to discuss with you some of the scientific advances that have been made this past year in the disease areas under the mandate of the Institute, and to share with you some of our future plans.

Osteoporosis, the leading cause of bone fractures both in postmenopausal women and in the elderly, affects approximately twenty-four million Americans. The NIAMS leads the federal research effort to conduct and support basic, clinical, and epidemiologic investigations on osteoporosis through individual research grants and specialized research centers. In February 1990, the Institute cosponsored a highly successful international conference entitled "Research Advances in Osteoporosis." The latest findings were presented, and recommendations for future research were developed. A new treatment-bisphosphonates--was shown to be very effective in combatting the bone loss of

osteoporosis.

The Institute continues to expand its research efforts in osteoporosis. Two requests for applications (RFAs) for research on osteoporosis are being issued. One invites additional basic research on fundamental causes. The second invites more grant applications on clinical and epidemiological research on osteoporosis. The Institute is also stepping up its disease prevention and health promotion efforts with regard to osteoporosis. The NIAMS Information Clearinghouse will expand its educational activities both for the public and for health professionals. Projects to inform consumers about risk factors, preventive measures, and research results are being planned.

There are more than 100 kinds of arthritis, affecting not only the joints

but other connective tissues of the body including important supporting structures such as muscles, tendons, and ligaments. One of the most common is rheumatoid arthritis, a chronic inflammatory disease afflicting more than 2 million adults in the United States. In recent experiments with rats, scientists have developed a T-cell vaccine that could ultimately lead to T-cell therapy and vaccination in humans. The Institute has also begun a clinical trial in which an antibiotic is being tested as a treatment for rheumatoid

arthritis.

In other recent research, a dissimilarity in tissue type between

mother and fetus has been found in many women with rheumatoid arthritis who improve during pregnancy. This finding suggests that the mismatch induces an immunologic reaction that suppresses the arthritis.

Lyme disease, which has both arthritis and skin disease among its major manifestations, has become a national problem. It is now the most common insect-borne disease in the Nation, and its distribution is worldwide. NIAMS is giving high priority to both research and outreach programs for Lyme disease. The Institute has recently funded several new basic research grants to increase understanding of how the infectious agent causes the disease, with the hopes of improving diagnosis and treatment, and providing the foundation for development of an effective vaccine. NIAMS is also supporting a clinical trial to determine if antibiotics can prevent Lyme disease from emerging in people who have been bitten by the deer tick. Programs to better inform both the public and health professionals about the dangers and prevention of Lyme disease are under way. A data base on educational materials was recently completed; and in early March 1991, a workshop on Lyme disease will be held with panels of experts to develop up-to-date vital information for physicians on both the diagnosis and treatment of Lyme disease.

One of the most exciting breakthroughs this year was the identification of a gene that causes a form of osteoarthritis, the most common form of arthritis, a disease in which the cartilage that covers and cushions the joints breaks down. NIAMS-supported investigators at two different grantee institutions, working together, isolated and characterized a faulty gene for collagen II, the main structural protein that strengthens cartilage.

HLA-B27 is

Another exciting breakthrough in arthritis this year was the successful induction, by transgenic transfer, into inbred rats of both the human gene (HLA-B27) for spinal arthritis and the entire clinical spectrum of the group of diseases (spondyloarthropathies) associated with spinal arthritis. found in over 90 percent of patients with spinal arthritis, and in only 8 percent of the general population. These diseases associated with spinal arthritis comprise the most common forms of arthritis in young men. The striking mimicry between the disease manifestations found in this animal model and those found in humans opens avenues for research, including the testing of

innovative therapies, that were unimaginable just a few years ago.

Ongoing NIAMS epidemiological investigation of Native Americans in Alaska and Siberian Eskimos--populations that have a high prevalence of spondylitis--promises to shed light on the roles of genetic factors and environmental triggers, such as bacterial infections.

Systemic lupus erythematosus (lupus) is an immune-mediated inflammatory disease that afflicts numerous Americans, largely young women, especially black women of child bearing age. The disease affects the skin, joints, kidneys, brain, and other organs.

Recently, a new antibody was identified that is

clearly associated with psychiatric disorders due to lupus; this antibody will

make better diagnosis possible.

The Institute has set up a task force to study lupus in high-risk populations.

With advice from the task force, NIAMS is developing instructive kits that will help health care providers and community organizations conduct health promotion programs targeted to young black women. The Institute also plans to sponsor an international workshop on systemic lupus erythematosus to assess current knowledge and develop directions for future research.

Scleroderma is a serious disorder of connective tissue and the fine blood

vessels.

Besides damaging the skin, muscles, and joints, the disease may also affect internal organs, such as the kidneys, heart, and lungs, making it lifethreatening in some people. Women are affected three times more often than men. The first symptom of scleroderma is usually Raynaud's phenomenon, wherein blood vessels in the fingers narrow as the result of vasospasm, causing the hands to become pale and cold. There is also pathologic evidence of vascular disease seen under the microscope. Accordingly, there is keen interest in exploring vascular abnormalities that may contribute to the etiology of the disease. NIAMS will issue a program announcement to stimulate more research on causal mechanisms in scleroderma.

Over 100 different conditions are included among the heritable connective tissue disorders, all of which stem from abnormalities of connective tissue, the scaffolding that girds bone, skin, blood vessels, and the protective coverings of internal organs. Although the disorders are uncommon, they are