Drugs get closer look as jaw damage appears among osteoporosis patients

McClatchy Newspapers (MCT) - After Geneva Grimpo fell and broke her hand and arm, doctors put the tiny, fragile-looking woman on drugs to strengthen her bones.

Three years into her drug therapy, trouble began.

Her lower jawbone poked out through sores on the left side of her mouth where her gums had decayed. The visible bone was dead, and she used her fingers to fish out tiny bits as they broke off.

"Now my right jaw hurts," said Grimpo, 85. X-rays show that bone is dying, too.

Her problem is a growing concern for dentists nationwide. It is called osteonecrosis of the jaw, or ONJ, a condition in which the gums become painful and infected, exposing underlying areas of dead bone in the jaw.

Dentists see ONJ in patients who take certain bone-strengthening drugs used to fight cancer or osteoporosis _ drugs that include Fosamax, Boniva and Actonel, some of the most-prescribed medications on the market.

In severe cases of ONJ, the infections lead to chronic pain. Decaying bone gives off a foul odor. Eating is difficult.

Even with regular treatment, these oral wounds can take up to two years to heal.

In 2003, medical reports began linking ONJ to a class of drugs called bisphosphonates. Soon after, the Food and Drug Administration required drug manufacturers to include an advisory about ONJ in their product labels.

The earliest cases of ONJ were found among cancer patients who took large intravenous doses of the drugs to keep their cancers from spreading to their bones.

Up to 10 percent of cancer patients taking bisphosphonates may develop ONJ, according to one estimate.

But ONJ also is showing up in otherwise healthy patients, like Grimpo, who take bisphosphonate pills when osteoporosis weakens their bones.

Doctors and dentists had assumed that ONJ among osteoporosis patients was exceedingly rare _ about 0.7 cases per 100,000 Fosamax users, according to one widely cited estimate from an American Dental Association panel.

But new research suggests that ONJ, while still uncommon, might afflict more osteoporosis patients. The specialists on the front lines who treat ONJ say they are seeing far more patients than past estimates predicted.

"I've had an explosion of patients," said Brett Ferguson, the chairman of oral surgery at the University of Missouri-Kansas City schools of medicine and dentistry. "No dentist in private practice wants to deal with this. It's a nightmare for them. They didn't learn about it in dental school."

Ferguson sees ONJ patients from throughout Missouri, Kansas and Arkansas. They began arriving at his Truman Medical Center clinic a few years ago. So far, he has seen more than 45 cases. While most are cancer patients, about one in five took oral bisphosphonates for osteoporosis.

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"They all say, 'Why me?'" Ferguson said.

Treatment can involve surgery to remove the exposed dead bone, long-term antibiotics, regular use of a prescription-strength antiseptic mouth rinse and scrupulous oral hygiene.

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One of Ferguson's ONJ cancer patients, a woman in her 70s, developed the condition after a dentist routinely extracted the teeth in her lower jaw. A month later, her gums separated from her jaw.

"Each place that got (extracted) would not heal," Ferguson said. "You could look in her mouth and see her jawbone, her dead jawbone."

Ultimately the woman had to be fed through a tube.

Another of Ferguson's patients, a woman who took bisphosphonates for osteoporosis, lost the bone of three tooth sockets in a row in her upper jaw, exposing her sinus cavity.

Ferguson couldn't fashion a prosthesis to fill the gaping space in her mouth for fear that attaching it would lead to more infection.

"You're left a dental cripple," he said.

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When dentists at the University of Southern California sensed that they were getting more ONJ patients than expected, researchers analyzed patient records.

"We had been seeing a greater number of cases over the past couple years. It just didn't fit with the idea that this doesn't exist as a problem," said researcher Parish Sedghizadeh.

In a study published in January in the Journal of the American Dental Association, Sedghizadeh and his colleagues went through the records of more than 13,000 regular patients at the dental school's clinic. They found 208 had been taking Fosamax, the most widely prescribed bisphosphonate brand for osteoporosis. Nine of these patients _ 4 percent _ had ONJ.

All the patients with ONJ had either tooth extractions or gum problems caused by ill-fitting dentures that exposed the jawbone and led to infection.

"We've been told that the risk of oral bisphosphonates is negligible, but 4 percent is not negligible," said Sedghizadeh, who thinks the numbers could increase in the years ahead.

Sedghizadeh said bisphosphonates can persist in the bone for a decade, and the risk of ONJ appears to rise with the dose.

"As we get more patients with 10 or 15 years' experience with bisphosphonates, we'll likely see more cases," he said. "We really haven't hit the top of the curve."

A statement by Merck & Co. Inc., which makes Fosamax, called Sedghizadeh's study flawed and unreliable as a source of valid conclusions about ONJ in patients taking the drug. Clinical studies of more than 17,000 Fosamax patients have found no cases of ONJ, the company said.

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While dentists are concerned about bisphosphonates, they are not advising patients to avoid them. For people with cancer, the medications are an important part of their treatment. And for those with osteoporosis, the drugs' benefits still far outweigh the risks.

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"They're really a valuable tool," said Barbara Lukert, an endocrinologist at the University of Kansas Hospital who prescribes bisphosphonates to her osteoporosis patients. "Fracture-related osteoporosis is a huge public health issue, and costly," she said.

About 40 percent of white women age 50 or older will experience a hip, spine or wrist fracture at some point in the remainder of their lives, Lukert said. Bisphosphonate therapy can reduce by about half the risk of spine and hip fractures, she said.

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Because so little research has been done, much about the ONJ-bisphosphonate connection remains a mystery: How many people have the condition? Who is most likely to get it? Why do the drugs harm the jaw far more often than other bones? How can the condition be prevented?

Scientists have known for decades that bisphosphonates can affect bones and have developed drugs to take advantage of the potential benefits.

The body's bones are constantly remaking themselves, being broken down by one group of cells and rebuilt by other cells. Bisphosphonates suppress the activity of the cells that break bones down. For osteoporosis patients, bisphosphonates give the bone-rebuilding process a chance to advance unopposed.

Because breast, prostate and multiple myeloma cancer cells tend to migrate to sites where bone has broken down, bisphosphonates can help keep these cancers from spreading.

Patients with cancer may develop ONJ more often than osteoporosis patients because the doses of bisphosphonates are so much higher in cancer treatment, said Mark Johnson, a biochemist at the UMKC School of Dentistry.

"They are using doses that are 10 times what are used to treat an osteoporotic patient. They're getting an annual dose on a monthly basis," he said.

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Johnson, Cielo Barragan-Adjemian and other UMKC researchers have done elaborate X-ray scans of the jaws of cancer patients who have taken bisphosphonates and developed ONJ.

They are finding that many of the patients have small areas of dead bone, a fraction of an inch in diameter, that are visible not just where sores appear, but throughout their jaws.

These findings suggest that ONJ could be seen as a dental disaster waiting to happen: Dead areas of jawbone lie under the gums. A tooth extraction or injury exposes the bone. The gums are unable to heal over the dead zone.

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"We think there's an underlying change in the bone. Bisphosphonates may be part of it that happens first" before symptoms appear, Johnson said. "It's like having a black box. You can't see what's in it until you take the lid off."

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Grimpo now is under Ferguson's care at Truman Medical Center, but when she first developed sores in her mouth, her dentist didn't diagnose her with ONJ.

"I just depended on my dentist, and I thought it was OK," said Grimpo, of Carrollton, Mo. "There's still a lot of dentists who don't what osteonecrosis is."

The University of Southern California study should serve as "a wake-up call to the dental community about the severe risk" posed by bisphosphonates, said Peter L. Jacobsen, a dentist and vice chairman of the American Dental Association's council on scientific affairs.

"All dentists should be asking their patients what medications they're taking. And if they're taking bisphosphonates, they have to alert patients about the risks and how to minimize them."

Dentists need to emphasize to patients who are on bisphosphonates the need for good oral hygiene and regular checkups to minimize the need for extractions and other dental work, Jacobsen said.

Patients who are about to start bisphosphonate therapy should have all their pending dental work done first, he said.

"But a dentist should never suggest that they not take bisphosphonates," Jacobsen said. "They are valuable drugs."

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© 2009, The Kansas City Star.