February 29, 1996
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Dental Researchers Work To Stop Bone Loss

Degeneration once seen as 'inevitable' now yielding to advances in pharmacology, molecular biology

Bone loss is a dental problem chronicled throughout history. Beginning with ancient writings of the Egyptians and Chinese, scholars have detailed the afflictions of people suffering tooth and bone loss. They have observed that as teeth are lost -- either from dental decay or periodontal disease -- the bony ridges of the jaws recede. This fateful erosion triggers one of the biggest problems in dentistry.

"The thin mandible can easily be fractured," said Ichiro Nishimura, associate professor of restorative dentistry at the School of Dental Medicine (HSDM). "Moreover, placing dentures or other dental restorations is very difficult, since there's no supporting structure."

Until recently, the general public accepted tooth and bone loss as an inevitable part of the aging process. But today, such attitudes are being challenged and changed. Advances in pharmacology and molecular biology are revealing new ways to stop bone loss, and also to regenerate bone.

At HSDM, a research team led by Nishimura recently identified a molecule that in animal studies appears to be involved in telling supporting bone where to grow in the jaw.

Other researchers, led by T. Howard Howell, acting chairman of periodontology and associate dean for dental education, are conducting clinical trials in humans to block the biological cascade that results in bone loss. They also are stimulating growth of new bone with new pharmaceutical agents developed with the latest biomedical technology.

"The need for advances in periodontal research is great," Howell said. "In fact, because preventative measures such as fluoridation have reduced the incidence of dental [decay], periodontal disease has assumed a greater importance as a cause of tooth loss. Today, periodontitis is the most common cause of the loss of teeth among adults."

A study conducted in 1986 by the National Institute of Dental Research found that persons from 55 to 64 years of age had lost an average of 10 teeth. In addition, approximately 15 percent of all seniors surveyed were completely toothless in at least one arch.

As a result, millions of people not only have reduced capacity for chewing, but also have aesthetic problems related to tooth loss. They also are at risk for extensive resorption (dissolution and re-absorption) of the alveolar ridge, the bone that holds the tooth sockets.

Fortunately, impressive advances in the past two decades have led to greater understanding of the cause and treatment of periodontal disease and alveolar bone loss. Many of those advances are emanating from HSDM.

Denture Dilemma

Nishimura's interest in bone loss and regeneration began as a graduate student at HSDM. Frustrated by attempts to fit dentures into the worn-away jawbones of toothless patients, he began thinking of ways to get new bone to grow.

He also was concerned that the wearing of dentures might actually make matters worse. A 1960 Australian study of institutionalized psychiatric patients showed those who wore their dentures faithfully had higher rates of bone resorption than those who refused to wear them at all.

Nishimura reasoned that the dentures themselves could be inflaming the jawbones and gums. This inflammation might be causing the release of bone-resorping factors.

He tested this hypothesis by giving anti-inflammatory agents to rats that had had their teeth removed. These agents inhibited the production of prostaglandin E2, a known bone-resorption factor. The effect was significant. "We inhibited up to 50 percent of bone resorption," he said.

But it was not known exactly how prostaglandins worked. Nor was it clear what other factors might be involved. Nishimura decided to look at how bone grows in the first place -- and the possibility of regenerating bone.

"If we can identify all of the components of bone formation and can reconstitute the bone blueprint in synthetic form, we could lay that down," Nishimura said. "The blueprint would use osteoblasts [bone-producing cells] to form bone as we design. It's designer bone."

This approach would solve several dental problems -- not only for would-be denture wearers and children with congenital facial deformities, but also for those considering tooth implants. Currently, patients undergoing tooth implantation must wait 6 to 10 months after extraction for their bone to heal before receiving implants. During this time, they must remain toothless. The rate of bone formation in implant patients, Nishimura speculates, could be accelerated.

While this research has raised considerable excitement among scientists, a major hurdle remains. "Bone cells that have been around for a while may have already gone through all their duplications already," said Nishimura. "When you ... say 'Make more bone,' they may not."

To find solutions to this problem, HSDM has formed a new Laboratory of Reconstructive Biotechnology. The challenge will be to coax bone cells to come out of retirement without becoming cancerous. "We have to tell them, 'Don't go into the graveyard yet. We want you to do one more big job,' " Nishimura said.

Bone-building Device

Howell and his colleagues at HSDM are trying other approaches to regenerate alveolar bone. A promising area of research focuses on growth factors -- proteins that occur naturally in the body, and hence harness the body's power to heal itself.

At HSDM, studies on dogs demonstrated that a combination of two growth factors, platelet-derived growth factor and insulin-like growth factor, can stimulate bone regeneration. Based on these results, HSDM researchers conducted the first study in humans to determine the safety and efficacy of using them.

In this study, 28 patients underwent periodontal flap surgery, with half the sites receiving surgery alone and half receiving a gel containing the growth factors. Compared with surgery alone, the sites treated with growth factor gel showed an increase in bone fill, particularly in the region of a tooth where the roots divide. Data from this study currently are being evaluated to design future studies.

In another study in conjunction with the Genetics Institute of Cambridge, Howell and his group are also studying another growth factor protein. This protein -- recombinant human bone morphogenetic protein-2, or rhBMP-2 -- is implanted in an absorbable collagen sponge within the bone site. Collagen is a common protein that makes up bone and cartilage.

"Our pilot study on dogs showed that rhBMP-2 has a positive effect on bone formation," said Howell, the study's principal investigator. The team subsequently did a pilot study of 12 patients to determine the safety and efficacy of using the rhBMP-2-collagen device in humans.

Conducted in collaboration with the University of Texas at San Antonio, the study showed that the device can be safely implanted in the defect site, won't migrate to another site, and can induce growth of new bone. To further investigate the effect of rhBMP-2, a larger clinical trial of the device is scheduled to begin this year.

"The thrust behind the combined work of HSDM researchers and other scientists is to develop ideal agents to stop the destruction and restore the alveolar ridge," Howell said. "Significant progress is being made on several fronts and it is just a matter of time before exciting, new treatment methods are available."

This article is adapted from a story in the most recent issue of Harvard Dental Bulletin.

 


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