Drug Eases Bone Cancer Pain in Mice

People with bone cancer say the pain they feel is worse than any other they’ve ever encountered. Pain becomes steady with time, and when a person simply moves a body part, a piercing pain sometimes interrupts the dull ache. It’s not uncommon for such breakthrough pain to arise from a mild touch to a person’s skin.

“It’s like a nail through the bone,” one patient told Patrick W. Mantyh, a neuroscientist at the University of Minnesota in Minneapolis.

Mantyh and his colleagues now report that in a study of mice, a novel drug already being tested for osteoporosis slowed the disruption of cells within cancerous bones and lessened the pain.

Within bones, cells called osteoblasts build bone mass while others, called osteoclasts, tear it down. Working in harmony, they keep the skeleton strong. However, in bone cancer, osteoclasts get the upper hand, and the acids they form dissolve too much bone, causing pain.

A drug called osteoprotegerin (OPG) thwarts osteoclast formation (SN: 1/15/00, p. 41:  Boning Up). To see if OPG diminishes bone cancer pain, Mantyh and his colleagues surgically inserted cancer cells into the thigh bones of 24 mice. After 5 days, 12 mice began receiving daily OPG shots, while the rest received inert injections. The researchers also observed 12 mice that underwent similar surgery but without getting cancer cells. Half of those mice then received OPG.

Mice respond to pain in many of the same ways that people do. After 17 days, the OPG-treated mice that had cancer showed less flinching, limping, and favoring of the cancerous limb than did the unmedicated mice with cancer, the researchers report in the May Nature Medicine.

A light touch induced only two-thirds as many flinches in OPG-treated mice as in animals getting inert injections and less than half as many turn-to-fight reactions.

Among the mice without bone cancer, no significant differences showed up between those that were and were not treated with OPG. When researchers compared all the mice getting OPG, those with cancer showed more signs of pain, indicating that some background pain persisted despite the medication.

“These data have salient consequences for the mechanisms that may underlie bone cancer pain and the therapeutic application of OPG,” say Stephen W.N. Thompson and David Tonge of King’s College London, writing in the same journal. They note that OPG treatment greatly eased pain induced by outside touch but appeared less effective against pain that seems to correspond to steady, or background, pain in people. They point out that background pain can be reasonably well controlled by treatment with opioids, synthetic mimics of opium-derived drugs such as morphine.

However, both natural and synthetic opiates have serious drawbacks. The body becomes inured to their effects over time, necessitating greater doses. Patients may also become sedated, cognitively impaired, and severely constipated.

Mantyh predicts that OPG will work against both background and breakthrough pain. If it does, patients could reserve opiates for the most severe pain. “The hope is they would be able to take significantly less morphine to avoid tolerance problems,” he says.

Breakthrough pain may arise because tumors give off chemicals that cause sensory nerves to perceive normal stimuli as harmful, Mantyh says. Some patients, for example, say combing their hair can be excruciating. Scientists aren’t sure why the nerve signals become so distorted, Mantyh says. By stopping bone destruction, OPG may help curb these errant signals, he suggests.

The researchers noted that osteoclast formation declined in the mice treated with OPG. They also observed fewer neurons that showed hypersensitivity to immune agents, a sign of persistent pain.

These measurements bolster the behavioral findings in the mice, says bone biologist Colin R. Dunstan of Amgen, the biotech firm in Thousand Oaks, Calif., that discovered OPG.

“I’m very hopeful that we’ll be able to treat patients with it,” says study coauthor Denis R. Clohisy, a surgeon also at Minnesota.

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