Anti-Cholesterol Drugs Offer Hope on Osteoporosis
A family of drugs already widely used to reduce cholesterol may provide the first effective treatment for osteoporosis, the bone-thinning disease that affects an estimated 28 million Americans.
Unlike existing treatments, which merely slow or delay bone thinning, the drugs, called statins, actually increase bone density, Texas researchers report in today’s Science.
Although the Texas team has only studied the drugs in mice so far, anecdotal reports from women using the drugs suggest that they may work in humans as well. The fact that the prescription drugs are already approved for use in humans means that clinical trials can be started quickly.
“This is unexpected but very exciting,” said Dr. Lawrence Raisz, an osteoporosis specialist at the University of Connecticut. “We have one or two other candidates in clinical trials, but this is a whole new approach to stimulating bone growth.”
“If we can show that it is effective, it would be a major advance,” said Dr. David S. Silver of the UCLA Osteoporosis Center. “These are very safe, widely used drugs, so it would be easy enough to do a clinical trial.”
A second group in Seattle has found the same thing, but has not yet published its results.
Osteoporosis, which affects four times as many women as men, is a major public health problem. It is responsible for about 1.5 million fractures annually, including 300,000 hip fractures and 700,000 fractured vertebrae. Many women who suffer such fractures are never able to live independently again, and the cost of caring for them in hospitals and nursing homes was about $13.8 billion in 1995, according to the National Osteoporosis Foundation.
Current treatments include estrogen replacement therapy and the so-called designer estrogens Fosamax and Evista, all of which slow bone loss. The hormone calcitonin has a similar effect.
Some people have touted the statins, which block the production of cholesterol by the body, as miracle drugs. A variety of studies have shown that they sharply reduce the risk of heart attack in people who have already had an attack, in people who have never had one, in people with high or medium cholesterol levels, and even in people with normal cholesterol levels.
They also reduce the risk of stroke and, statistically, the risk of death from all causes, although how they would do this is unknown. About 8 million Americans now take one of the six different statins on the market.
But their potential application in osteoporosis is a shock to many people.
Dr. Greg Mundy of the University of Texas Health Science Center in San Antonio established a company called OsteoScreen to search for natural products that could stimulate the production of a specific growth factor that targets bone. The factor--called bone morphogenetic protein, or BMP--was discovered in 1965 by Marshall Urist of UCLA, but clinicians have not yet been able to make use of it.
Mundy’s team screened more than 30,000 natural products and found only one that promoted BMP production. That was lovastatin (marketed as Mevacor), a molecule derived from a strain of fungus. Other statins on the market, which theoretically would produce the same results, are chemically similar compounds produced in the laboratory.
“The statin discovery came out of the blue,” Mundy said at a news conference Thursday. “We did not expect it.”
Nand Baindur of the biotech company ZymoGenetics Inc. in Seattle reported similar results at an American Chemical Society meeting in March, but he has not yet published his findings. Company officials contacted Thursday would not say whether they are conducting animal experiments.
After discovering lovastatin’s effects in the Texas screening program, Mundy and his colleagues demonstrated that it promoted the growth of bone cells grown in dishes.
Next, they injected it into the skulls of young mice. After the mice were injected three times a day for five days, their skulls were 50% thicker.
Finally, the team administered lovastatin or a related drug, simvastatin, orally to female mice whose ovaries had been removed so the animals were estrogen-deficient, mimicking post-menopausal women. After the animals had received either drug for 35 days, their leg bones and vertebrae were twice as dense as those of animals receiving placebos.
The team studied the medical records of 598 elderly women who were taking statins. They found that the women taking the drug had greater hip bone mineral density and a lower risk of hip fractures than women not taking the drugs. But the number of women studied was too small for a definitive conclusion, Mundy said.
Adverse reactions to the statin drugs, which act chiefly on the liver, have been mild and brief; they include constipation and insomnia. But experts warn against overprescribing the drugs to the elderly, who are more susceptible to liver damage.
Mundy also cautioned that none of the statins now available may prove to be the best drug for promoting bone growth because they are all targeted at the liver, and the amount of drug that reaches the bones is small. But pharmaceutical companies should be able to make other variants that will be drawn to bones, he added.
Two new treatments that were hoped to promote bone growth are in clinical trials, but it is not clear that they will be useful. Slow-release sodium fluoride has been shown to promote increases in bone density, but the new bone is apparently not of good quality, Silver said, and the treatment does not reduce the risk of fractures.
Researchers also are studying intermittent injections of a naturally occurring chemical called parathyroid hormone. Findings from those trials are not yet available, but one manufacturer has already dropped out of them, suggesting that the results are not promising.
Raisz and Silver said they hoped that physicians would not prescribe statins for osteoporosis patients until clinical trials have been completed. But Silver conceded that if he had such a patient who also had high cholesterol, “it would be interesting to see what happened.”
