Stockholm, Sweden -- The scientist who discovered that statins have the biological effect of restoring bone mass has called for randomized, controlled clinical trials to demonstrate that statins have a protective effect against osteoporotic fractures. At the XIIth International Symposium on Atherosclerosis held in Stockholm, Dr Gregory Mundy (University of Texas Health Science Center, San Antonio, Texas) presented data on his basic research, commented on four new observational studies on statins and their beneficial effects on bone, and outlined the need for future research.

"There's a tremendous potential here, with one pill, to benefit the lives of a large segment of the aging population which is only going to grow in size," Mundy said in an interview here. "Osteoporosis is a common disease among people who also would benefit from a statin as far as lipid lowering is concerned." "We want to try to find ways of delivering statins to bone so that more gets to bone," Mundy said. "We want to determine all the steps that are involved in the statin's effects on bone, how they work, and what the steps are between its inhibition of the cholesterol synthesis pathway and its effects on this growth factor gene."

Four Additional Observational Studies

He noted that four observational studies are appearing this week from four different groups on the effect of statins in protecting against fractures. "All these studies suggest there's a markedly lower risk of developing fractures when taking statin drugs," he said. He characterized these studies as "encouraging."

"The data we have so far is tremendously encouraging, but it takes a randomized clinical trial and dose-ranging studies to know how to best give the statins for bone," Mundy said. He added, "It's also necessary to learn which statin is best for bone."

Two of the new reports appeared in the June 23, 2000 issue of The Lancet. A study by Dr K Arnold Chan (Brigham and Women's Hospital, Boston) found that the use of statins appears to be protective against osteoporotic fractures in women older than 65. Chan has said he was inspired by reading Mundy's paper in Science last year which showed that statins increase new bone formation in vitro and in vivo. A second article in The Lancet from Dr C J Edwards (St Thomas's Hospital, London) reported a significant increase in bone mineral density in postmenopausal women who took any one of several statins to lower their cholesterol.

Background to the Research

In his quest for a drug that is truly anabolic for bone, Mundy first developed a screening assay to identify substances which stimulate the formation of new bone. Bone cell growth and proliferation occur naturally through the bone cells' own local production of a specific growth factor, BMP-2. Mundy's idea was to look for drugs that would promote the cells' production of BMP-2. He used a special bone cell line, maintained in vitro, that mimics the behavior of normal bone cells. He inserted an artificial gene into these cells, comprising the promoter region of the BMP-2 gene and the expression region of the firefly luciferase gene. He was then able to identify a collection of compounds that stimulated this glow-in-the-dark reporter system.

"When we screened about 100,000 compounds, we identified an extract containing a statin that was very active on the screen," he said. "Other inhibitors of HMG-CoA reductase, statins, were identified from the collection, and the more potent statins, in particular cerivastatin and atorvastatin, were among the most potent and efficacious bone stimulants," Mundy said. (At present, other commercially available statins include simvastatin, fluvastatin, pravastatin, and lovastatin).

Once the statins were identified by the screening assay, he conducted a large number of experimental studies, in vitro and in vivo, to demonstrate that the statins actually had a biological effect on bone.

Dose/Efficacy Trials in Humans Coming Soon?

Mundy noted that rats are a very good model for studying osteoporosis but a very bad model for studying lipids. He said that the doses he used in the rat studies were higher, weight for weight, than would be used in humans. "We'll have to wait and see what the most effective dose will be in humans, but my hunch is that it's going to be in the same range as is now used for lipid lowering," Mundy said. "It's possible we will see effects at even lower doses than those used for lipid lowering."

Pat Phillips
www.athero.org