Dec. 6, 1999 A team of scientists has discovered that some widely-prescribed cholesterol-lowering drugs also have impressive bone-building capabilities that may make them effective drugs for treating osteoporosis. The team's findings appear in the 3 December issue of Science.
These drugs, known as statins, represent an entirely new approach to treating osteoporosis, one which emphasizes building new bone to replace bone that has already deteriorated. Current therapies for the disease focus on stopping or slowing bone loss and stabilizing a person's existing bone mass.
"Hopefully this will stimulate drug companies to take a look at the statins that they might have on their shelves and do clinical trials on the ones that actually target bone," said Gregory Mundy of Osteoscreen, lead author of the study.
100 million people worldwide are at risk for osteoporosis, particularly postmenopausal women and a rapidly growing elderly population. In osteoporosis patients, bone loses crucial minerals such as calcium and phosphorus and becomes thin and fragile. Fractures of the hip and pain and compression in the spine are some of the most common problems associated with the disorder. Osteoporosis patients have often lost 50 to 60 percent of their bone mass in these crucial areas, so rebuilding this bone is key to their recovery, according to Mundy.
The team of scientists also included Ross Garrett, Jeannie Chan, Di Chen, Giovanni Rossini, Ming Zhao, and Gloria Gutierrez, all from Osteoscreen, as well as Stephen Harris of the Department of Medicine at the University of Texas Health Science Center and Brendan Boyce of the Department of Pathology at the University of Texas Health Science Center.
Mundy and his colleagues identified the statin group as potentially powerful agents against bone loss after an extensive, three month search of over 30,000 natural compounds. Their goal was to find small molecules that could activate the gene for a protein that promotes bone formation. Out of 30,000 possibilities, statins proved to be the only ones that specifically increased levels of the bone formation protein.
As they are conventionally prescribed, statins work by blocking the action of an enzyme in the liver that turns fatty foods into cholesterol. Studies show that statin drugs dramatically lower cholesterol levels in high cholesterol patients, reducing rates of coronary heart disease and stroke and lowering the risk of dying from these diseases. Statins such as lovastatin, simvastatin, pravastatin and others have been widely used for over ten years with little toxic side effects, marketed under names like Mevacor, Zocor, and Prevachol.
The research team first applied four different types of statins to bone taken from the skulls of mice and grown in a laboratory culture. Each of the statins increased bone growth in the cultures two to threefold by stimulating the production of osteoblasts, the specialized cells that create new bone.
"The statins build up a team of osteoblasts, but in addition to that, they bring these osteoblasts into maturity, so they can start growing bone," Mundy said. This is in contrast to most current bone loss therapies, which only increase the number of osteoblasts without encouraging the differentiation and maturity of these bone-building cells.
After this initial success, the researchers tested the effects of statins in living animals, first injecting the drugs directly into the tissue overlying the skullcaps of mice. They also administered oral doses of the statins to two groups of female rats, one group with intact ovaries and another group with the ovaries removed to mimic the effects of menopause. The mice that were directly injected showed an almost 50 percent increase in new bone formation in the skull after only five days of treatment. In the oral dose groups, the statins caused increases in new trabecular bone (the type of bone found at the ends of bones like the femur) ranging from 39 to 94 percent after approximately one month's treatment.
"It was totally amazing to us," Mundy said of the amount of bone growth, "especially the effects of it in culture and applied locally."
He noted that the less dramatic increase in bone growth for the oral dosage groups was probably due to the fact that the orally-administered statins don't make their way to the targeted bone as well as those that are directly injected. Since statins are designed to zero in on the liver, most of their effects on bone are secondary. For these statins to be really effective as agents against osteoporosis, Mundy said, they need to be the kind of statins that distribute themselves directly to bone or bone marrow.
Although the statins seem to be most effective at building new bone, the researchers could not rule out the possibility that the drugs were also inhibiting the breakdown of bone, which could make them a candidate for osteoporosis prevention as well.
A preliminary analysis that looked back at a group of elderly women taking statins to lower their cholesterol found that these women had higher bone mineral density and less fractures in their hip. However, Mundy cautioned that this retrospective analysis is not definitive, since the overall sample size was small and there were no controls on the length of treatment or the consistency of the statin doses. The real answer to how well these statins contribute to bone formation in humans will come after randomized clinical trials, he said.
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