By Melissa Knopper

Gloria Rivera had multiple myeloma involving her ribs, skull, and spine. At a loss for words when trying to describe the bone pain she endured daily, she described it as “worse than labor.”

“If you’ve ever had a dentist hit a nerve when he’s filling your tooth—it’s that intensity of pain, but it doesn’t stop,” said Rivera, who lived until Aug. 23 of this year.

By contrast, breast cancer survivor Rosalie Benson, 63, of Richmond, Virginia, felt no symptoms, despite bone metastases on her spine, ribs, sternum, and pelvis. “I live a pretty normal life,” she says. “I’ve had no recognized bone pain.”

Bone metastasis (cancer cells that break off a main tumor and start to grow on bones) is a common complication associated with certain types of cancer—especially breast, prostate, lung, kidney, thyroid, and multiple myeloma. It can be extremely painful and require surgery. For other patients, such as Benson, bone metastases can be relatively mild if diagnosed and treated early. Many cancer patients develop bone metastases at some point during the course of their disease.

Signs and Symptoms
The most common sites for bone metastases—hips, femur, pelvis, and spine—may have to do with blood flow, says Allan Lipton, MD, oncologist and professor, Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania.

Bone metastases can occur when cancer cells that have lodged in the bone cause small areas of bone to wear away, creating small holes called osteolytic lesions. This porous bone, similar to that of an osteoporosis patient, becomes fragile and prone to breaks. In other patients, the tumor may cause extra calcium to build up abnormally and form areas of new bone called osteosclerotic lesions, which can be painful and may lead to fractures.
Bone metastases are painful because migrating cancer cells irritate sensory nerve fibers in the bone, Dr. Lipton says. Some patients must live with excruciating discomfort, while others have milder symptoms.

Patricia LeClair, a 58-year-old resident of Omaha, Nebraska, has breast cancer that metastasized to her lower back, describing the pain as feeling a lot like osteoarthritis.

When treated appropriately with all available tools, most patients with bone metastases should have good pain control. But if the bone metastases weaken the bone enough to cause a fracture, the pain becomes even more severe. Fractures may be avoided if doctors make an early diagnosis, says Dr. Lipton. If a break does occur, it can be repaired with a surgical implant or a cast.

When cancer metastasizes to the spine, it can cause spinal cord compression, a severe complication in which the growing cancer squeezes the spinal cord causing possible numbness or weakness in the legs, numbness in the abdominal area, trouble with the bowel or bladder, or even paralysis.

“When it happens, it can be a disaster,” Dr. Lipton says. “If it’s not picked up early, people may have to spend the rest of their days in bed.”

Rivera, who was not properly diagnosed at first, had cancer that nearly ate away two of her vertebrae. “There was a toothpick holding up my spine,” she said. Surgeons repaired Rivera’s back with a titanium cylinder and a bone graft.

Patients with bone metastases also face the danger of high blood calcium levels (hypercalcemia). This occurs when calcium is released into the bloodstream from the degrading bones. Early signs include loss of appetite, thirst, and fatigue.

If cancer cells spread to the bone marrow, they may cause a decline in red or white blood counts. A drop in red blood cells results in anemia, causing fatigue, weakness, and shortness of breath. Signs of low white cells include fever, chills, fatigue, or pain. Abnormal bleeding can occur if the number of platelets drops.

Diagnosis
To find bone metastases, a doctor may start with an X-ray or a bone scan. But, as Rivera learned, they do not always show up on X-rays. Her lesions only appeared when she asked for magnetic resonance imaging (MRI).

“A CT [computed tomography] scan or an MRI will show you the bones better because they can differentiate osteoporosis from tumor,” Dr. Lipton says. If doctors still aren’t sure, they may biopsy the bone tissue.

The usual screening test for bone metastasis, a bone scan, is much more sensitive than X-rays and reasonably inexpensive. MRI and CT scan are more sensitive than bone scan, but are more expensive.

Doctors and patients say early diagnosis is key. “By the time it gets to the point where it causes pain, it can be pretty far along,” LeClair says.

Benson is grateful that her oncologist at Massey Cancer Center in Richmond did a bone scan when she was first diagnosed with breast cancer in 1996. She says that early, pre-symptomatic detection and treatment for bone metastases probably prevented subsequent debilitating bone pain.

Treatment With Bisphosphonates
In most cases, physicians use bisphosphonates, a class of drugs given intravenously that slows abnormal bone destruction and formation, to ease bone metastasis pain, reduce fractures, and prevent new lesions.

“We initially thought these drugs simply mucked up the osteoclast, the Pac-Man cell that gobbles up [old or fatigued] bone, but we now know the process is more complex,” says James Berenson, MD, Institute for Myeloma and Bone Cancer Research, Los Angeles. “There are data emerging that suggest bisphosphonates are antitumor drugs that directly kill cancer cells.”

Oncologists previously used a drug called Aredia® (pamidronate), which is given intravenously once a month. But now, they also have a more potent bisphosphonate, Zometa® (zoledronic acid), which is infused in 15 minutes, compared with two hours for Aredia. LeClair, who has taken both, prefers Zometa. “It cuts down your time in the chemo room,” she says.

A recent study compared Zometa and Aredia in 1,648 breast cancer and multiple myeloma patients with at least one bone lesion. After approximately two years of follow-up, those taking Zometa had a 16% reduced overall risk of developing bone metastasis compared with those taking Aredia.

In addition, Zometa is indicated for treatment of bone metastases due to prostate cancer, breast cancer, multiple myeloma, and solid tumors, including lung, renal, and colorectal cancers. Aredia, on the other hand, is only indicated for breast cancer and multiple myeloma. Side effects for both drugs are similar and can include mild fever, chills, and fatigue for a day or two. Less common side effects of bisphosphonates include risk of damage to kidney function. Bisphosphonates and conventional treatments (chemotherapy or hormonal therapy) complement each other and are preferably used in combination.

Radioisotope-Based Treatments
Bone-seeking radioisotopes offer a good alternative for painful bone metastases, particularly for patients who have significant side effects from pain medication, says Oliver Sartor, MD, director of Stanley S. Scott Cancer Center, New Orleans. The best candidates have the type of metastasis that builds deposits on the bone (osteosclerosis) instead of creating holes (osteolytic). Patients with a bone scan positive for bone metastasis are usually good candidates for this type of therapy. Patients also must have reasonably good blood counts and no history of severe kidney problems, he adds.

Two radioisotopes are on the market. Metastron® (strontium-89) acts like calcium and accumulates broadly in bone with an emphasis on areas with metastases. Bone pain relief is relatively slow in onset but may last three to six months from a single injection. Quadramet® (samarium-153) is a newer radioactive isotope that reduces bone pain. Patients may experience relief as soon as one week after the single injection, and studies have shown pain relief typically lasts up to four months.

“Seventy percent of patients respond, and half of the responders will have complete or marked relief of pain,” Dr. Sartor says. If bone pain recurs, Quadramet can be re-administered every three to four months provided blood counts have recovered. These two radioisotopes have been combined with chemotherapy drugs in experimental trials in an effort to make each therapy more effective.

Most of the studies with Quadramet and Metastron were performed in prostate cancer patients. The role of these agents in the management of breast cancer is less well-defined. In addition, aggressive use of pain medication, sometimes in combinations, is imperative to obtain optimal pain control and maintain the highest quality of life.

New Drugs
By studying how and why some tumors spread to bone instead of other organs, researchers hope to some day stop bone metastasis altogether. While they have not yet reached that ultimate goal, scientists have developed some promising new drugs, says Gabriel Hortobagyi, MD, chairman of the department of breast medical oncology, M. D. Anderson Cancer Center, Houston. The most useful new compounds now being tested in clinical trials include:

• Osteoprotegerin (OPG) is a protein made by the body to help preserve a healthy balance between cells that build up bone tissue (osteoblasts) and cells that tear it down (osteoclasts). When bone metastasis occurs, that balance is upset, causing too much bone loss. Scientists use a synthetic OPG that interferes with the signals between osteoclasts and osteoblasts to tip the balance in favor of stronger bones. The drug has had good results in phase II clinical trials. Physicians measured a significant reduction in the typical markers of bone loss that appear in blood and urine, Dr. Hortobagyi says. Phase III studies of OPG in patients with bone metastasis are currently ongoing.

• Parathyroid hormone-related protein (PTHrP) can be made by some tumor cells and poses a threat to people with bone metastases because it stimulates osteoclasts and can result in hypercalcemia. To prevent this bone destruction, researchers created CAL-02, a humanized monoclonal antibody that binds to PTHrP to make it inactive.
  
  “It’s like putting chewing gum onto a key so you can’t put it into the keyhole anymore,” Dr. Hortobagyi explains. In phase I clinical trials, this antibody had positive results. “A couple of my patients who were in severe pain had a very rapid decrease in pain after treatment with the antibody,” Dr. Hortobagyi says. “It appears very, very promising.” Next, Dr. Hortobagyi’s team plans a study comparing anti-PTHrP antibody to bisphosphonates.
  

• Src kinase is a gene linked to the spread of cancer to the bone. Researchers are developing compounds to suppress it, and hopefully, slow bone metastasis. Progress is coming more slowly in this area, Dr. Hortobagyi says. Src kinase may also play beneficial roles within a cell, so scientists must be cautious.
  
  “Just imagine Src as being a traffic light at a very busy intersection where six streets converge,” he says. “If you turn off the traffic light, imagine the mess it would create. We are trying to determine whether it would interfere with other types of signaling.” So far, Src kinase inhibitors have effectively prevented bone loss in animals, but few human studies are available.

For most cancer patients, the initial diagnosis is the most emotional and traumatic. But, as the disease unfolds, bone metastasis has the potential to severely affect quality of life. It can cause pain, increase the need for drugs, and lead to surgery and radiation. For that reason, doctors and patients say it pays to be extremely vigilant: Insist on an early diagnosis and the best technologies and treatments.

LeClair says, “You really have to be proactive about your own case.”