Bone Drugs May Harm What They're Supposed To Protect

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Bone drugs may harm what they're supposed to protect

The bisphosphonate drugs have been linked to death of bone tissue.

Bones may seem solid, the sturdy frame that supports our soft and spongy flesh and insides. But at the cellular level, bone is in constant flux. Cells called osteoclasts chomp away at it, discarding the proteins and minerals they can't use into the bloodstream. (Bone's loss is the body's gain - those proteins and minerals get used elsewhere.) Osteoblasts are the constructive counterforce - think b for builder - the busy cellular masons that work to fill the voids left by osteoclasts.

When we're young, 'clast versus 'blast comes out pretty even, and our bones benefit from the standoff because they are being perpetually remodeled and rejuvenated. But with age, the osteoblasts flag and the osteoclasts gain the upper hand. The result is thinner, therefore weaker, bones that are more likely to break when we fall or have some other mishap.

Bisphosphonates as the equalizer

The bisphosphonate drugs - the best known of which are alendronate (Fosamax) and risedronate (Actonel) - are supposed to help bring osteoclasts and osteoblasts back into a healthy equilibrium. They rein in osteoclasts by speeding up apoptosis, or programmed cell death, so the cells die off faster. They also jam cell-to-cell signaling that goads osteoclasts into action.

Millions of people take oral bisphosphonates for osteoporosis, the thinning of bone that's usually related to advancing age, and Paget's disease, a bone disease. Bisphosphonates, usually administered intravenously, are also used extensively in cancer treatment. Blood cancers, especially multiple myeloma (a cancer of the plasma cells), secrete substances that rev up osteoclasts. Other types of cancer (breast, kidney, lung, prostate) damage bone directly once they've metastasized and infiltrated it.

Intravenous bisphosphonates are also used to treat hypercalcemia - too much calcium in the blood. About 10%-20% of cancer patients develop the condition, which can be life-threatening if it gets out of control. The bisphosphonates slow the breakdown of bone tissue, the source of the extra calcium, and may, as an added bonus, hamper the growth of cancer cells.

IV dosages are up to 12 times higher than the oral drugs. Patients get infusions every few weeks and sometimes take the drugs for years. The FDA has approved two IV bisphosphonates, pamidronate (Aredia) and, more recently, zoledronic acid (Zometa).

Reports of osteonecrosis

Reports of a possible link between the bisphosphonates and death of bone tissue, or osteonecrosis, began to surface in 2003. But it was Dr. Salvatore Ruggiero and his colleagues at Long Island Jewish Medical Center who put the issue on the map a year later with a study published in the Journal of Oral and Maxillofacial Surgery. Reviewing records at their hospital and the University of Maryland, they identified 63 patients with osteonecrosis of the jaw that seemed to be related to bisphosphonates. Most were cancer patients; multiple myeloma (28 cases) and breast cancer (20 cases) were the most common diagnoses. But they also found six cases involving people who took oral bisphosphonates for osteoporosis.

Ruggiero's study triggered more investigations. In 2006, Dr. Sook-Bin Woo, a researcher at the Harvard School of Dental Medicine, and two colleagues summarized findings from 10 studies (including Ruggiero's) and several smaller ones. The picture that emerged from their review is similar to that sketched by Ruggiero. The jaw is affected (see sidebar), and IV, not oral, bisphosphonates are the main culprits. About 85% of the cases involved people with multiple myeloma or metastatic breast cancer, and about 60% occurred after a dental surgery to treat infections, such as getting a tooth pulled.

Why the jaw? So far, the osteonecrosis that's associated with bisphosphonates has been almost exclusively limited to the upper (maxilla) and lower (mandible) jawbones. No one is sure why. Jawbone tissue itself doesn't seem to have any special properties that would make it susceptible. But the jawbones are exposed to a lot of minor trauma (from chewing) and threats of infection from bacteria in the mouth, with only a thin sheath of gum tissue for protection. A minor cut or sore creates an opening. If bisphosphonates dampen bone metabolism and reduce the tissue's normal healing ability, they may make the jawbones vulnerable to damage from trauma and infections that they would ordinarily withstand. But bone tissue sometimes dies for reasons unrelated to a detectable infection. Doctors call this aseptic necrosis. Some cases of bisphosphonate-related osteonecrosis seem to fall into this category. Osteonecrosis of the jaw

How common is it?

A definitive prevalence study hasn't been done. In the meantime, less conclusive studies have found that up to 10% of multiple myeloma patients treated with bisphosphonates are affected, and nearly as many breast cancer patients.

No one has firm figures for the oral bisphosphonates either, although there's no question that the risk is far less than it is for the IV drugs. While noting that cause-effect hasn't been established, the American Dental Association has estimated 0.7 cases of osteonecrosis will occur for every 100,000 "person-years" of exposure to oral bisphosphonates. That would mean about 20 cases per year in the United States, according to a rough estimate by Athanasios I. Zavras, an assistant professor at the Harvard School of Dental Medicine.

Zavras and a colleague used the records of a large national insurance company to check for an association between bisphosphonate use and major oral surgery (a good, if imperfect, indicator for osteonecrosis) among cancer patients. They found that people who received IV bisphosphonate therapy were four times more likely to have had jaw surgery as those who didn't. They found only a 15% increase in risk among oral bisphosphonate users that wasn't statistically significant. Even if it was, the finding may not be applicable to the vast majority of people taking oral bisphosphonates for osteoporosis.

Why does it happen?

Like bone and most everything else in our bodies, the circulatory system is far from static. Small blood vessels are constantly being created (or pruned away) to bypass blockages in existing vessels and to meet fluctuating blood demands. Bisphosphonates seem to retard the growth of new blood vessels; the medical term for this is antiangiogenic. This property may help account for their value as cancer drugs: They help deny tumors the blood they need to grow and spread. But it's bad for bones if the bisphosphonates are choking off their blood supply as well.

Bisphosphonates may push all bone tissue into a sluggish state, not just the destructive osteoclasts. As a result, bone may lose the ability to fend off routine infections and to heal properly from normal wear and tear.

It's also possible that several factors need to come together. Chemotherapy agents and corticosteroids (which are also known to be hard on bone) may combine with the bisphosphonates to create a toxic tipping point. The cancer itself may play a role. Dental procedures, or the underlying infection that led to them, may deliver the crowning blow to bone tissue that's already in trouble.

Treatment

Once bone tissue is dead, there's nothing that can be done to bring it back. In advanced cases of osteonecrosis of the jaw, the tissue is quite soft and can be surgically removed easily, but that may not stop remaining tissue from dying, possibly because the underlying infection is still active. In fact, some experts say cutting out the dead bone could make the condition worse.

Patients are often treated with long-term intravenous antibiotic therapy. Sometimes, strong prescription mouthwashes (Peridex, PerioGard) that contain chlorhexidine are prescribed.

Hyperbaric oxygen treatment hasn't proven to be very effective. The treatments in pressurized chambers are supposed to hasten healing by forcing more oxygen into the blood.

So what should you do?

For cancer patients, intravenous bisphosphonates pose a dilemma often seen in medicine: The risk from a medication is quite real, but so are the demonstrated benefits. The tradeoff can't be eliminated entirely, but precautions can be taken. In this case, dental surgery often seems to be the precipitating factor, so cancer patients are supposed to get serious dental problems like impacted wisdom teeth taken care of before, or soon after, they start getting intravenous bisphosphonate infusions. Once they've been getting the treatments awhile, dental surgery should be conservative and do the least amount of damage to jawbone tissue as possible. Regular checkups and cleanings are more important than ever.

It's been harder to come up with suggestions for people taking oral bisphosphonates for osteoporosis and Paget's disease. The evidence so far is that the risk is so small - some might say vanishingly so - that doing anything differently might be an overreaction. Yet given a choice, why not be on the safe side?

In June 2006, the American Society for Bone and Mineral Research made some helpful preliminary recommendations. Like cancer patients, osteoporosis and Paget's disease patients should consider getting invasive dental procedures done before they start bisphosphonate therapy. Doctors should inform patients about the osteonecrosis risk, and patients should tell their dentist that they're taking the drugs.

It's an open question whether taking a break from bisphosphonates before and after dental surgery makes sense. It may not make much difference. Bisphosphonates continue to have an effect long after people quit taking them because they get deeply incorporated into bone tissue. The antiangiogenic effects, though, may wear off soon after the drugs are stopped.

Even if oral bisphosphonates aren't much of a risk, this is an opportunity to think about other ways of protecting your bones. Weight-bearing exercise, which includes walking, does wonders: Working your muscles stimulates bone tissue, so it stays healthier. And many of us don't get as much vitamin D as we should. The recommendation is 600 IU daily. We probably should be getting closer to 800, even 1,000 IU.

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Last updated:	August 22, 2006