Stopping A Slow, Insidious Process
William Pierce explores new ways to stop bone loss and breakage due to osteoporosis.
You just broke a bone.
You may not have felt it, but it happened. It happens to everyone constantly. In fact, everyday activities such as walking, running and lifting cause painless, microscopic fractures.
Fortunately, most people won't need medical attention.
That's because bone breakdown is a natural part of the body's maintenance. Cells called osteoclasts constantly break down bone while cells known as osteoblasts replenish it.
"Too often we think of bone as a static tissue, but in reality it's very dynamic," says William Pierce, a U of L pharmacology and toxicology professor.
However, Pierce is concerned with a harmful process going on in the bones of millions of people: osteoporosis.
It's usually thought of as a condition affecting older women after menopause, yet everyone is at risk. Loss of calcium and a lack of hormones such as estrogen are leading causes, but there are many more. The slow loss of bone over the course of years can eventually lead to bone breakage.
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U of L researchers involved in a company called Pradama, formed to develop and market osteoporosis drugs, include from left, pharmacology and toxicolgy professors Leonard Waite and William Pierce, chemistry professor K. Grant Taylor and research associate Jason Neale.
Various treatments to stop bone loss have been developed in recent years based on antibiotics, estrogen or compounds known as bisphosphonates. Another is hormone replacement therapy. Newer therapies include treatment with other hormones.
Yet, according to U of L pharmacology and toxicology professor Bill Pierce, these treatments may all have detrimental side effects or other drawbacks.
"Bisphosphonates, one of them is the brand Fosamax, which is taken orally as a pill and works pretty well, but there are problems with administration," he explains. "These are relatively strong acids and if you don't use them properly they can erode tissues in the esophagus. You have to take it with a big glass of water and stay upright a half-hour and you can't eat or it's not absorbed. Also, it can stay in the body's tissues a long time before being fully excreted. Newer treatments, such as Forteo, must be taken as an injection."
Pierce and research colleagues have worked 20 years to find an osteoporosis treatment that can target and bind to bone cells with few or no side effects and which can be administered conveniently in pill form.
He believes that he and his colleagues have developed such a treatment, and U of L has applied for two "composition of matter" patents with the federal government to protect their discoveries and eventually market drugs based on them.
The discoveries come after years of trial and error, testing and rejecting many compounds along the way.
"We reverse engineered a tetracycline, or antibiotic, molecule, which is very effective at finding bone tissue," Pierce says.
"Then we came up with a couple of compounds that will bond to bone material and hooked those up to estrogens," he continues. "Estrogens are known to decrease the rate of bone breakdown. But we needed an estrogen that was smart enough to effect only the bone without increasing the risk of tumor development in the breast and uterus."
Pierce says testing is continuing on compounds that pose almost no increased risk of breast and uterine cancer development.
"We plan to target a whole variety of hormones and other drugs that have the potential to target any molecule," he adds. "That would help us develop other possible treatments. For example, a more localized drug that could accelerate bone- fracture healing.
"We've been able to show in animal models that these compounds not only appear to stop bone loss, but can even stimulate bone formation in rats," Pierce says.
Pierce foresees a time when such a compound could help astronauts stop the severe bone loss that occurs in space's zero gravity.
"Right now space travel beyond six to 12 months is impossible because so much bone is lost," he says. "If you have no stress on bone, which happens in weightlessness, you lose the bone."
Investigators included in the patent with Pierce are U of L pharmacology and toxicology professor Leonard Waite and U of L chemistry professor K. Grant Taylor. Jason Neale, Pierce's research associate, also is a key partner in the research and shareholder in any future royalties that might result from patents.
Once the U.S. Food & Drug Administration reviews and approves the team's work for further study, phase-I human trials can begin, Pierce says. "It takes millions of dollars and lots of fundraising and grant support to develop drugs like this," Pierce says. "That's why we have formed a startup company called Pradama with the help of MetaCyte to develop and market these drugs commercially."
MetaCyte Business Lab LLC is a for-profit unit of the Louisville Medical Center Development Corp. that supports health-related startup companies. U of L Health Care was a partner in the lab's incorporation. U of L's Office of Technology Transfer has licensed the technology to Pradama. U of L and the investors stand to receive royalty payments from any commercial applications of the osteoporosis drug research.
"Osteoporosis is a slow, insidious process that goes on without a person even knowing it," Pierce says. "Too many people find out when it's too late—when catastrophic mechanical failure of the bone occurs. A minor slip, and a bone breaks.
"We hope to not only stop bone loss but completely reverse it."
In the meantime, Pierce recommends simple advice that lessens osteoporosis risk.
"Eat calcium and Vitamin D. Exercise. Walk. Run. Put stress on the bones. The bones need it. And we all need to exercise anyway."
