Fighting bone loss
Research breakthrough offering hope to osteoporosis patients
by Will Sansom
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Gregory R. Mundy, M.D., professor of medicine, has discovered that statins, which are found in drugs taken to lower cholesterol levels, may help those suffering from osteoporosis by increasing bone formation. |
These magnified views of normal bone (top) and osteoporotic bone (below) show the loss of bone density that occurs with osteoporosis. |
After testing 110,000 compounds, something had to give. Gregory R. Mundy, M.D., professor of medicine, and his company,
OsteoScreen, were panning for a golden nugget—an agent to stem the tide of bone loss in osteoporosis and other disorders. "We tested compounds in two classes, including 35,000 natural product extracts, searching for active ingredients," he said. "Then we tried the statins, which are extracted from a type of yeast." Already widely used as cholesterol-lowering drugs, these compounds proved to be the proverbial nuggets in the prospectors' pans. Dr. Mundy and his colleagues announced their findings to the public. In the prestigious journal Science, they reported that cells from statin-treated laboratory rodents showed dramatically increased bone formation - possibly enough to prevent fractures in the animals. Worldwide response was immediate; even today the researchers are answering national and international requests from scientists, clinicians, patients, industry and the media concerning the possibilities of statins. These compounds, already taken daily by 3 million Americans in drugs such as the cholesterol-fighting Lipitor(tm), could one day be adapted to help the millions of Americans and others worldwide who suffer from the bone-thinning disorder called osteoporosis. Today's patients and physicians would love to have another treatment option. Antonia Treviño, 74, travels to the Texas Diabetes Institute (TDI) on the West Side for appointments with Health Science Center endocrinologist Jan Bruder, M.D., assistant professor of medicine. The TDI is part of the University Health System. "Mrs. Treviño suffers from established osteoporosis with low bone density and spine fractures," Dr. Bruder said. "We recently started her on estrogen replacement therapy and calcium and vitamin D supplements. But these only prevent further breakdown and loss of bone; they do not replace what she has lost." Treviño's calling was to be a mother to 14 children. Throughout her 74 years in Mexico and Texas, she performed the household chores, the cooking and cleaning and laundry and more, for her sizable family household. But a spine fracture seven years ago abruptly curtailed her active lifestyle. "We went to my niece's wedding and she fell down the steps at the church," said Maria Treviño, translating for her mother during a visit with Dr. Bruder. "An MRI later revealed the fracture. After that, she was in a hospital bed at home for a year and then in a wheelchair for another year. It was very painful for her to go to doctor appointments." The elder Treviño has never heard of statins, but she knows that two other members of the family also had osteoporosis. The possibility of subsequent fractures is haunting. She misses her mobility and time spent at the kitchen stove, which is not recommended because it means standing on her feet. She misses cooking her specialties which were chilé relleno, fritada (made with baby goat) and tamales. Gone also are the days when she and her husband, Gonzalo, went camping, hunting or fishing. "She was a good shooter, better than my dad," Maria Treviño said. Dr. Bruder, like Dr. Mundy, is intrigued by the possibility that statins might enhance bone formation. She hopes to do a three-month pilot research study in women with normal and low bone densities to see if a drug regimen including statins will indeed increase the blood markers of bone formation and bone density. Dr. Mundy, meanwhile, continues his work in the laboratory and speaks on the topic around the world. "Nature offers powerful therapeutic possibilities," he said. "Many drugs come from natural substances, such as the heart medicine, digoxin, which is derived from foxglove; one of the oldest antibiotics, penicillin, which comes from mold; and the recently developed cancer drug, taxol, which is derived from the bark of the Pacific yew tree. "Pharmaceutical industries scrape natural products from ocean floors and rainforests and then screen them, and screening is what we were doing. The compound that was most active in bone formation at the cellular level was an extract containing lovastatin, one of the older-generation cholesterol drugs." Statin amounts tested in the rodents were higher than doses taken by humans through anti-cholesterol medications, Dr. Mundy said, noting, however, that extrapolating the results of the laboratory study to humans is not scientifically valid. Even so, the identification of statins and subsequent testing of their effects could be extremely important in preventing osteoporosis and alleviating other bone-related disorders. "I've received many messages since our paper was published in Science," Dr. Mundy said. "One woman, whose fracture had not healed in years, reported it did so after she was put on a cholesterol-lowering statin drug. Of course, we can't say scientifically that statins were the cause of her improvement. A man sent a message reporting a problem with a loose tooth implant. When he went on a statin drug, his implant became fixed in place and the dentist noticed obvious bone growth around the tooth, the man wrote. If our findings are validated in humans, statins might prove very helpful in the area of dental implants." The statin finding has huge financial ramifications, as well. At $5 billion a year, Lipitor is one of the best-selling pharmaceuticals ever. The drug is known to lower LDL, the so-called "bad" cholesterol, and reduce the frequency of heart attacks. It is so successful that one pharmaceutical company, Pfizer, recently bought another, Warner-Lambert, to obtain the rights. Six statin drugs currently are on the market, with an estimated sales of more than $10 billion annually. "If the statins are as good at preventing osteoporosis as they are at reducing cholesterol, this new clinical use could double their sales," Dr. Mundy noted. "And we tested one of the older statin drugs. It looks like the newest statins have a more powerful effect on bone than their predecessors." The Health Science Center researchers hope to shed light on how statins increase bone formation. These agents are known to lower cholesterol at the cellular level by limiting production of an enzyme that is integral to cholesterol synthesis.
"We found that as a consequence of the same enzyme being inhibited in bone cells, a growth factor is increased that makes bone-forming cells mature," Dr. Mundy said. "We're trying to work out the actual mechanisms by which that happens in the cell and we are collaborating with the laboratory of Dr. Bettie Sue Masters in those studies." Bettie Sue Masters, Ph.D., is the Robert A. Welch Professor in Chemistry in the Health Science Center's Department of Biochemistry. During their two-year search, the scientists systematically ruled out chemical compounds that have known effects as well as natural agents whose effects were not known. "We were sifting through a haystack and found a needle," Dr. Mundy said. Put another way, they found gold, and the rush soon may be on to help people, such as Antonia Treviño, who suffer from the risk or actual incidence of bone-thinning disorders. |
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