By David N. Leff

As everybody knows, heart disease is the No. 1 killer in industrial societies, and cholesterol is its smoking gun.

The half-dozen drugs that lower cholesterol - to wit: Mevacor (lovastatin), Pravachol (pravastatin) and Zocor (simvastatin), Baycol (cerivastatin), Lipitor (atorvastatin) and Lescol (sluvastatin) - have been on the market for a decade, and at times seem to be the top stars of TV commercials. Although pricey - typically $60 for a month's supply - these prescription tablets have proven highly effective in controlling cholesterol levels in people at risk of atherosclerosis.

What's more, the drugs themselves are relatively risk-free. "Though they do have side effects," observed endocrinologist Gregory Mundy, "these cholesterol-lowering statins are remarkably safe drugs, and many millions of people have taken them. As far as I can tell - certainly from the literature that's written about them - side effects are unusual; they're rare."

Mundy has just contributed to that literature by discovering a new, unexpected and potentially beneficial side effect in these drugs. His report appears in today's issue of Science, dated Dec. 3, 1999, under the title: "Stimulation of bone formation in vitro and in rodents by statins."

Mundy, the paper's principal author, is a full-time faculty member at the University of Texas Health Science Center in San Antonio, and founder/CEO of OsteoScreen (OS), a small spin-off company in that city. "We have a very large bone-biology group at the university," Mundy told BioWorld Today, "and OS, which we set up in 1988, was an offshoot of that, specifically to do early-stage drug discovery for common bone diseases - osteoporosis and cancers that spread to bone.

"The current direct treatment of osteoporosis," Mundy went on, "is aimed only at preventing further deterioration. But the problem is that people who've got osteoporosis have lost maybe 50 percent of the bone - maybe more - at critical sites in their skeleton. So the ideal drug treatment would be anabolic agents, which rebuild bone architecture rather than just stabilizing remaining bone mass and preventing further bone resorption.

Turning From Injectables To Orals

"We began about 10 years ago," Mundy recounted, "looking for potential drugs to do this. We started up with peptides, the growth factors that are actually in bone, and can have powerful effects in experimental animals to stimulate bone formation.

"But we found the problem is that these peptide growth factors work not only for bone but for other tissues in the body as well. That has its inherent risks, and - being peptides - they must be injected. This is not something that's tolerated well, particularly by old people, who'd much prefer to have an oral medication."

So about five years ago, Mundy and his colleagues changed their strategy. "We decided we'd search for small, orally available molecules, which would actually stimulate growth-factor production locally within bone. We developed a simple, high-throughput, screening assay, based on one of these bone growth factors, bone morphogenic protein 2 (BMP-2), with the goal of identifying small molecules that would enhance new production within bone cells. We screened something like 65,000 small molecules, and a collection of about 35,000 natural products. One of the natural-product extracts was very powerful, very effective. We identified the active principal, and it turned out to be lovastatin, which is a drug that is not only on the market, but used by 3 million Americans." (Nature extracted lovastatin first - from a fungal strain of Aspergillus terreus.)

"We didn't believe it at first," Mundy recalled. "We thought it must be a contaminant in that particular broth, but it wasn't. So we then bought some lovastatin commercially, extracted it from the tablets, and tested it. Then we tested some other statins - related drugs - and confirmed that they also had biological effects in bone.

"After assaying them in organ culture systems, we went to in vivo animal models of osteoporosis. That's really the subject of this Science paper. What it says is that statins, which prevent heart attacks by inhibiting cholesterol synthesis, have this totally unanticipated effect of stimulating bone formation by enhancing the production of this key growth factor, BMP-2, within bone cells."

From these striking results in rodents, the next logical step was to sample some of the millions of Americans who have routinely swallowed lovastatin tablets to lower their cholesterol, and see what welcome side effect that regimen may have had on their geriatric bone disorder.

"Our collaborators scanned a database," Mundy recounted, "of something like 18,000 patients who have been followed for osteoporosis around the country. Unfortunately, as it turned out, people who take statins are not by and large the postmenopausal women we follow for osteoporosis. The tablets are taken mostly by middle-aged or older men, concerned about their cholesterol levels."

In that database they found 598 women, in whom, Mundy observed, "It certainly looked like a trend toward the patients taking lovastatin being better off in terms of their mineral density at the hip, and subsequent risk of hip fracture.

"The trick with the statins," he pointed out, "is going to be making sure that they get to bone. And the problem is that the current cholesterol-lowering statins on the market are extracted preferentially by the liver, so only small amounts reach bone.

"We need an alternative mode of administration to bypass the liver," Mundy said. "And one possibility is to administer statins in a patch preparation. If they're absorbed across the skin, they get straight into the bloodstream, and thus end-run around the liver.

"That's where things stand right now," Mundy summed up. "This suggests that the statins offer a new approach to treatment of osteoporosis. What's clearly required right now, I think, is a randomized clinical trial to see if they are really as effective in people as they are in rats."

He expressed the hope that the paper in Science, as well as a press conference Thursday at the editorial offices of that journal, "will generate enough interest that some of the pharmaceutical companies may decide to look among the statins sitting on their shelves that they haven't developed for cholesterol-lowering. So there may be a wonderful drug for bone that's sitting on the shelves of a statin pharmaceutical firm right at the moment," Mundy concluded. "They obviously need testing."