Experiments in mice with a bone disorder similar to osteoporosis after menopause show that an overlooked group of cells are likely crucial to the process of bone loss caused by the disorder, according to a study published online ahead of print October 5 in Nature Medicine. The finding, researchers say, not only raises the research profile of the cells, called preosteoclasts, but also explains the success and activity of an experimental osteoporosis drug currently in phase III clinical trials.
“We didn’t know that the drug affects preosteoclasts, nor did we understand how important preosteoclasts are in maintaining healthy bones,” says Xu Cao, PhD, the Lee H. Riley Jr., MD, Professor of Orthopaedic Surgery at Johns Hopkins University in Baltimore. “Now drug companies hoping to reverse osteoporosis can look for even more drugs that make use of and target these interesting cells.”
Xu Cao, PhD
Dr. Cao and colleagues grew two cell types separately in the laboratory and collected the liquid around them to test for proteins released by the cells. They found that preosteoclasts, but not mature osteoclasts, secrete platelet-derived growth factor-BB (PDGF-BB). When the preosteoclasts of mice were prevented from making PDGF-BB, the mice had weak bones.
When the mice were given L-235, the animal form of odanacatib, the numbers of their preosteoclasts and osteoclasts increased, and they secreted more PDGF-BB. The increased PDGF-BB brought in more cells for making blood vessels and bone, which led to more of the specialized blood vessels and thicker bones.
To see if the drug could help reverse the increased bone resorption and decreased blood vessel formation of postmenopausal osteoporosis, the investigators simulated menopause in female mice by removing their ovaries.
At first, the mice had thinner bones and fewer blood vessels, but treatment with the drug increased the concentration of PDGF-BB in the blood, the number of specialized blood vessels both inside and outside of the bones, and the overall thickness and density of the bone.
According to Dr. Cao, in addition to slowing bone resorption by blocking cathepsin K, the drug also appears to slow the maturation of preosteoclasts, lengthening the amount of time they secrete PDGF-BB before becoming osteoclasts. With increased PDGF-BB, more specialized blood vessels are made and more bone-building cells arrive, restoring the balance between bone resorption and bone rebuilding.
Odanacatib is produced by Merck & Co. Inc. (Whitehouse Station, New Jersey) and has already gone through phase III clinical trials with good results, according to Dr. Cao.
“It is unusual to see a single drug that decreases bone resorption and increases bone rebuilding at the same time,” Dr. Cao said.