Encouraging findings on several different drugs were presented Thursday at the CTRC-AACR San Antonio Breast Cancer Symposium in Texas.

First in the line-up, the osteoporosis drug zoledronic acid (Zometa) appears to shrink breast tumors in patients who undergo chemotherapy.

The drug is already approved to treat breast cancer that has spread to the bone and, earlier this year, was reported to lower the risk of breast cancer recurrence in pre-menopausal women with early estrogen- or progesterone-positive tumors.

In an analysis of slightly more than 200 women, those who received Zometa in addition to chemotherapy had better results than those receiving chemotherapy alone. After compensating for variables such as estrogen receptor status and treatment duration, residual invasive tumor size was 42.4 millimeters in the chemotherapy alone group, and 28.2 millimeters in the combination group.

“This data suggests that zoledronic acid is doing something more than protecting bone,” said study senior author Dr. Robert Coleman, a professor of medical oncology at the University of Sheffield in England. “It’s not practice-changing. It’s hypothesis-generating, which will lead to the design of new trials to look at this in detail. But this is the first patient-related evidence.”

Coleman spoke, along with researchers involved with other trials, at a Thursday teleconference. Other studies showing promise included:

Postmenopausal women with estrogen receptor- and/or progesterone receptor-positive breast cancer who took the aromatase inhibitor exemestane (Aromasin) had a 15 percent relative reduction in recurrences and a 19 percent reduction in the risk of distant metastasis, compared with those taking tamoxifen alone. “Exemestane is very effective at preventing recurrences,” said Dr. Stephen Jones, medical director of U.S. Oncology Research in Houston. Exemestane, like other aromatase inhibitors, blocks production of estrogen, while tamoxifen, long the gold standard in breast cancer therapy, inhibits the hormone’s effects in the body.Seventy percent of women receiving Herceptin (trastuzumab), a drug used to treat HER2-positive breast cancer, plus chemotherapy

before

surgery survived three years without a recurrence. Only slightly more than half of women receiving chemotherapy alone survived that long. The incidence of major heart problems was low. “Herceptin given before surgery with chemotherapy significantly [reduces the likelihood] of a recurrence in patients with advanced HER2-positive cancer, and most likely will translate into a benefit in terms of survival,” said Dr. Luca Gianni, director of medical oncology at the National Cancer Institute in Milan, Italy. “We think that this data establishes preoperative Herceptin with chemotherapy as a standard treatment option for women with advanced HER2-positive breast cancer.”Combining lapatinib (Tykerb), another HER2 inhibitor, with an aromatase inhibitor (in this case, letrozole) prolonged progression-free survival from three months among those taking letrozole (Femara) alone to 8.2 months in women taking both drugs. These patients had HER-2-positive metastatic breast cancer. “The combination shows benefits in controlling the disease and controlling it for longer than using endocrine therapy alone,” said Stephen Johnston, a consultant in medical oncology and reader in breast cancer medicine at Royal Marsden Hospital and Foundation in the United Kingdom. “The suggestion is that combined therapy may be the best approach.”Finally, aromatase inhibitors may be poised to replace tamoxifen as standard treatment to prevent breast cancer recurrence in women who have already undergone conventional therapy, according to a new meta-analysis. The analysis looked at two groups: women with postmenopausal estrogen receptor-positive breast cancer who took tamoxifen for five years after standard treatment and women who took tamoxifen but then switched to an aromatase inhibitor after initial treatment. “The data are still early but it does show a statistically significant advantage in [women who were switched from tamoxifen to an aromatase inhibitor] but not in [women who took tamoxifen for the full five years],” said Dr. James Ingle, director of the breast cancer program at the Mayo Clinic, in Rochester, Minn. “But you have to remember our experience with tamoxifen. It took 10 to 15 years to see the full effect of tamoxifen.”

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That study, released in the Sept. 11 issue of the New England Journal of Medicine, suggested that those who underwent the surgery didn’t fare any better in the long run than their counterparts who received physical therapy. During the surgery, small incisions are made through which a small camera and surgical instruments are inserted. Physicians can then repair or remove cartilage, or flush the knee to remove debris — or do both procedures.

The trick is to find one or more treatments — amid the array that includes medication and physical therapy — that can ease the pain of worn cartilage. It can take some work.

“When patients come into my office,” says Dr. Ronald Grelsamer, a knee surgeon in the orthopaedics department at Mount Sinai School of Medicine in New York, “I give them a list of 17 options to help them manage their condition. At the very bottom is arthroscopy. It works for a little while, but it’s not going to cure it. . . . What I’ve found is that nothing works for everybody, and everything works for somebody.”

Oral nonsteroidal anti-inflammatories, such as Celebrex, can reduce inflammation and pain, as can cortisone injections. Hyaluronic acid injections can replace some of the viscous synovial fluids that lubricate the joints but that sometimes decrease with age. Acupuncture and massage may also alleviate pain. But as people get older and knees become more worn, the ultimate remedy could be a total knee replacement.

And although a New England Journal of Medicine study in 2006 found that glucosamine and chondroitin supplements fared no better than a placebo among 1,583 people in reducing knee pain by 20%, some doctors still recommend it. “The average effect is quite small,” says Dr. John FitzGerald, assistant professor of rheumatology at the David Geffen School of Medicine at UCLA, “and it can be slow-acting. That study is open to interpretation; I think on average it works a little bit for some people.”

But much can be said for consistent exercise, which can also tamp down pain and improve mobility, according to health experts. One study published in the Annals of Internal Medicine compared a physical therapy program of manual therapy and exercise with a placebo program of subtherapeutic ultrasound, and it found that exercise improved walking distance and function, pain and stiffness scores far greater than the placebo.

Shed some pounds

A good first line of defense, health experts say, is shedding some pounds. “You can get some long-lasting effects,” FitzGerald says. Even a little makes a huge difference, because walking and running can put extra force — equivalent to several times one’s body weight — on the knees with every step. “Even with 5 to 10 pounds, which is a reasonable goal, people can expect a fairly significant improvement in knee pain,” he says.

The recommendation comes with a snag, however: When knees hurt, the motivation to exercise goes south.

“Unfortunately, you can’t wait for the knee to get better to start exercising,” FitzGerald says. “Start exercising, and then the knee will get better.”

Laura Bennett, a physical therapist who works with osteoarthritis patients at L.A.’s Good Samaritan Hospital, has a use-it-or-lose-it philosophy when it comes to battling osteoarthritis.

“If we don’t use it, we lose strength in our muscles and range of motion,” she says. “We can compensate for a while, but if we become stagnant in our movements, then our joints don’t get the fluid they need, which means they don’t get the nutrition they need, then arthritis sets in, and it hurts to move, so we don’t want to move.”

Walking, swimming and water workouts are great for some with arthritic knees, Bennett says. “Being in the water takes a certain amount of body weight off the knees and hips. Joints have an easier time moving and the water gives muscles some resistance.” Walking time and intensity should progress gradually, she says. Many physical therapists will examine patients’ muscle strength and flexibility from their feet to their hips and back, plus assess alignment and gait, possibly prescribing exercises and stretches to correct disparities and weaknesses.

“A lot of times with osteoarthritis,” Bennett says, “it could be a muscle imbalance that’s causing it, where one side might be weaker and one side is tighter, and people are not working at a biomechanical advantage.” It’s also not just the knees that are worthy of attention — other joints that support them, such as the hips and ankles, are important to shore up as well.

Depending on the person, therapy might include a hamstring stretch that can be done sitting or lying down (stretching muscles helps increase joint flexibility). In that move, a belt is looped around one foot and the straightened leg lifted until a stretch is felt along the back of the leg. This can be repeated three times and held for 30 seconds on each leg. External hip rotators, which are part of the kinetic chain that supports the knee, can be strengthened by lying on one side with knees bent, the top leg raised like a clamshell. (Note: No exercises should be attempted before consulting with a physician or licensed physical therapist.)

Take a load off

In examining movement patterns during walking or running, Christopher Powers, associate professor of biokinesiology and physical therapy at USC, looks for “dynamic misalignment,” checking to see if knees fall inward or if there’s an abnormal rotation at the hip or foot. These, he says, can put undue torque and stress on the ligaments, joints and cartilage. Therapy, he adds, can take some of those stresses off the knee joint.

Because biomechanics vary from one person to the next, therapy programs need to be tailored but may include working with patients to change their gait — not always an easy task, considering that walking is something most people do automatically. “The patient has to be aware of what they’re doing and why they’re doing it,” he says.

“Your muscles are kind of like shock absorbers,” Powers adds, “and when they’re not working well, you start to rely on your passive shock absorbers, like your cartilage and bone.”

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Pun absolutely intended, Dr. Thomas B. Dodson explains, ” ‘Bisphosphonate-related osteonecrosis of the jaw’ is a mouthful.” His expertise is another mouthful — oral and maxillofacial surgery at Massachusetts General Hospital. He’s an expert on . . . let’s just call it BRONJ.

The problem has been linked to drugs called bisphosphonates, ranked 10th in U.S. sales among all drug categories, according to IMS Health, which analyzes pharmaceutical and healthcare markets. Most cases come after someone has been treated for cancer with potent, intravenous forms of the drugs. About 1 in 10 cancer patients treated with IV bisphosphonate develops the jaw problem.

But a handful of cases have shown up in women taking much smaller doses of the drugs for treatment of osteoporosis.

Bisphosphonates, marketed as Actonel, Actonel+Ca, Aredia, Boniva, Didronel, Fosamax, Fosamax Plus D, Reclast, Skelid and Zometa, are meant to increase bone density in the short run by reducing the bone-loss part of the bone life cycle. But some scientists think the drugs may eventually hurt the jaw’s ability to heal after, say, a tooth extraction or a dental implant.

The estimates on the number of people who might experience the jaw problem range from 1 in 2,000 to as many as 1 in 300 people who take the drugs for osteoporosis.

In the U.S., 55 million prescriptions for bisphosphonates are written annually, according to a 2007 report in the journal Osteoporosis International. Even if not all of those prescriptions are filled, and even if many of the women who start taking the drugs stop, the number of women who might have trouble in dentists’ chairs is sure to rise.

Most commonly, those people will see or feel some exposed bone in the mouth, as the dead bone works its way through gum or tissue, but without pain. In those cases, people are simply told to use an antibacterial mouthwash. If there’s pain or discomfort, and the area of exposed bone is small, a dentist will try to smooth down the exposed area.

In rare cases, the area of dead bone is large. “Then people run the risk of breaking the jaw, because the area is so large,” Dodson says.

So why would a medicine that circulates through the entire body result in a pharmaceutical punch to the jaw? Researchers have only theories.

It could be, Dodson says, that bone in the jaw metabolizes at a speedier rate than in other parts of the body so more of the drug is getting deposited there. And because there is more bacteria in the teeth and mouth area, that could add to inflammation, worsening the problem.

Or it could be, he says, that the mechanism of the drug is at work. Bisphosphonates inhibit cells that dissolve bone. “But dissolving bone is part of a healthy life cycle,” he says. The natural balance between dissolving bone and making new bone is disrupted and bone-producing cells now dominate. But when they die off, there are fewer cells to clean them out, and they remain, a dead mass.

Dental procedures — tooth extraction, dental implants, oral surgery — can increase the risk of a problem because of trauma to the jaw. That’s why the American Assn. of Oral and Maxillofacial Surgeons recommends that if a woman is going to begin taking a drug for osteoporosis, she have dental work done before she starts.

If she’s been taking the drug for three years or more, the association recommends a three-month drug holiday before having non-emergency oral surgery.

But for women who’ve been on the drug, an urgent problem — such as a throbbing toothache — should be dealt with immediately, even though there may be a 1 in 300 chance that she has BRONJ.

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