Osteonecrosis of the Jaw

Osteonecrosis of the jaw (ONJ) has been reported in patients with cancer receiving treatment regimens including bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. The majority of reported cases have been associated with dental procedures such as tooth extraction. Many had signs of local infection including osteomyelitis.

A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, corticosteroids, poor oral hygiene).While on treatment, these patients should avoid invasive

In a December 13, 2004 press release, doctors at Long Island Jewish Medical Center (LIJ) announced that they had discovered a link between bisphosphonate drugs and osteonecrosis of the jaw (ONJ), or literally, death of the jaw bone tissue.

Bisphosphonates are a class of drugs used to treat osteoporosis as well as prevent the metastasis of certain cancers into the bones. They lessen the body’s ability to resorb bone, a process that naturally takes place in order to allow new bone cells (called osteoblasts) – to occupy the skeletal structure. The names and manufacturers of the most popular bisphosphonate drugs are: Zometa (generic name: Zoledronate) and Aredia (Pamidronate) manufactured by Novartis AG; Fosamax (Alendronate) is from Merck & Co.; Actonel (Risedronate) and Didronel (etidronate), products of Procter & Gamble Pharmaceuticals. Zometa and Aredia are administered intravenously. Fosamax and Actonel are oral bisphosphonates and are often used in cancer patients.

THE STUDY CONFIRMING THE LINK

The discovery of the link between ONJ and bisphosphonates was published in the Journal of Oral and Maxillofacial Surgeon. The report prompted both the U.S. Food and Drug Administration (FDA) and bisphosphonate drug maker Novartis AG to issue warnings to physicians and dentists about the risk for the potential adverse effect. A letter published in the same journal in 2003 was the first report of a signal that ONJ was associated with bisphosphonates.

The chief of the Division of Oral and Maxillofacial Surgery at LIJ, Salvatore Ruggiero, MD, DMD, or doctor of dental medicine, said they conducted the study after they noticed a cluster of cancer patients with necrotic lesions in the jaw, a condition they previously saw in only one or two patients a year. In conducting a review of the patients’ charts, the doctors found that the 63 patients, diagnosed with ONJ over a 3-year period, shared one commonality, they all had received long-term bisphosphonate therapy.

Between February 2001 and November 2003, 63 patients were diagnosed and 56 of them were cancer patients who had received infusions of bisphosphonates for at least a year. Seven other patients had been receiving long-term oral therapy for osteoporosis.

“The patients developed ONJ after normal bone trauma,” the press release said, “such as a tooth extraction, while receiving bisphosphonate therapy.” Rather than healing, the bone began to die, and a majority of the patients required surgery to remove the diseased bone.

Another study released on April 4, 2006, found that more than 2,400 patients who were taking the injected form of bisphosphonate had suffered bone damage to their jaws since 2001. In addition to the 2,400 patients who were taking the injected form, the study found 120 patients taking the oral form of the drug who had been stricken with such incapacitating bone, joint, or muscle pain that some became bedridden and others required walkers, crutches or wheelchairs.

While the number may seem small when compared to the estimated 39 million oral prescriptions written in 2005, the problems still indicated a trend and may have signaled a serious problem for long term use of bisphosphonates.

“We’ve uncovered about 1,000 patients (with jaw necrosis) in the past six to nine months alone, so the magnitude of the problem is just starting to be recognized,” Kenneth Hargreaves, of the University of Texas, told the newspaper.

WHAT WAS THE FDA RESPONSE?

In August 2004, the FDA’s Office of Drug Safety issued its Postmarketing Safety Review on about four bisphosphonate drugs used to treat osteoporosis: Fosamax, Zometa, Aredia, and Actonel. The FDA report concluded that warning language about adverse events involving osteonecrosis should be added to the drugs’ labels.

On September 24, 2005, Novartis issued a “Dear Doctor” letter regarding Zometa and Aredia, indicating that patients on injected bisphosphonate therapy should avoid invasive dental procedures, and that a dental examination should occur before initiating intravenous bisphosphonate therapy. The letter quoted the new precaution to be placed in the product label in August 2004. Precautions

Osteonecrosis of the Jaw

Osteonecrosis of the jaw (ONJ) has been reported in patients with cancer receiving treatment regimens including bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. The majority of reported cases have been associated with dental procedures such as tooth extraction. Many had signs of local infection including osteomyelitis.

A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, corticosteroids, poor oral hygiene).While on treatment, these patients should avoid invasive

THE STUDY CONFIRMING THE LINK

The discovery of the link between ONJ and bisphosphonates was published in the Journal of Oral and Maxillofacial Surgeon. The report prompted both the U.S. Food and Drug Administration (FDA) and bisphosphonate drug maker Novartis AG to issue warnings to physicians and dentists about the risk for the potential adverse effect. A letter published in the same journal in 2003 was the first report of a signal that ONJ was associated with bisphosphonates.

The chief of the Division of Oral and Maxillofacial Surgery at LIJ, Salvatore Ruggiero, MD, DMD, or doctor of dental medicine, said they conducted the study after they noticed a cluster of cancer patients with necrotic lesions in the jaw, a condition they previously saw in only one or two patients a year. In conducting a review of the patients’ charts, the doctors found that the 63 patients, diagnosed with ONJ over a 3-year period, shared one commonality, they all had received long-term bisphosphonate therapy.

Between February 2001 and November 2003, 63 patients were diagnosed and 56 of them were cancer patients who had received infusions of bisphosphonates for at least a year. Seven other patients had been receiving long-term oral therapy for osteoporosis.

“The patients developed ONJ after normal bone trauma,” the press release said, “such as a tooth extraction, while receiving bisphosphonate therapy.” Rather than healing, the bone began to die, and a majority of the patients required surgery to remove the diseased bone.

Another study released on April 4, 2006, found that more than 2,400 patients who were taking the injected form of bisphosphonate had suffered bone damage to their jaws since 2001. In addition to the 2,400 patients who were taking the injected form, the study found 120 patients taking the oral form of the drug who had been stricken with such incapacitating bone, joint, or muscle pain that some became bedridden and others required walkers, crutches or wheelchairs.

While the number may seem small when compared to the estimated 39 million oral prescriptions written in 2005, the problems still indicated a trend and may have signaled a serious problem for long term use of bisphosphonates.

“We’ve uncovered about 1,000 patients (with jaw necrosis) in the past six to nine months alone, so the magnitude of the problem is just starting to be recognized,” Kenneth Hargreaves, of the University of Texas, told the newspaper.

WHAT WAS THE FDA RESPONSE?

In August 2004, the FDA’s Office of Drug Safety issued its Postmarketing Safety Review on about four bisphosphonate drugs used to treat osteoporosis: Fosamax, Zometa, Aredia, and Actonel. The FDA report concluded that warning language about adverse events involving osteonecrosis should be added to the drugs’ labels.

On September 24, 2005, Novartis issued a “Dear Doctor” letter regarding Zometa and Aredia, indicating that patients on injected bisphosphonate therapy should avoid invasive dental procedures, and that a dental examination should occur before initiating intravenous bisphosphonate therapy. The letter quoted the new precaution to be placed in the product label in August 2004. Precautions

Osteonecrosis of the Jaw

Osteonecrosis of the jaw (ONJ) has been reported in patients with cancer receiving treatment regimens including bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. The majority of reported cases have been associated with dental procedures such as tooth extraction. Many had signs of local infection including osteomyelitis.

A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, corticosteroids, poor oral hygiene).While on treatment, these patients should avoid invasive

Between February 2001 and November 2003, 63 patients were diagnosed and 56 of them were cancer patients who had received infusions of bisphosphonates for at least a year. Seven other patients had been receiving long-term oral therapy for osteoporosis.

“The patients developed ONJ after normal bone trauma,” the press release said, “such as a tooth extraction, while receiving bisphosphonate therapy.” Rather than healing, the bone began to die, and a majority of the patients required surgery to remove the diseased bone.

Another study released on April 4, 2006, found that more than 2,400 patients who were taking the injected form of bisphosphonate had suffered bone damage to their jaws since 2001. In addition to the 2,400 patients who were taking the injected form, the study found 120 patients taking the oral form of the drug who had been stricken with such incapacitating bone, joint, or muscle pain that some became bedridden and others required walkers, crutches or wheelchairs.

While the number may seem small when compared to the estimated 39 million oral prescriptions written in 2005, the problems still indicated a trend and may have signaled a serious problem for long term use of bisphosphonates.

“We’ve uncovered about 1,000 patients (with jaw necrosis) in the past six to nine months alone, so the magnitude of the problem is just starting to be recognized,” Kenneth Hargreaves, of the University of Texas, told the newspaper.

WHAT WAS THE FDA RESPONSE?

In August 2004, the FDA’s Office of Drug Safety issued its Postmarketing Safety Review on about four bisphosphonate drugs used to treat osteoporosis: Fosamax, Zometa, Aredia, and Actonel. The FDA report concluded that warning language about adverse events involving osteonecrosis should be added to the drugs’ labels.

On September 24, 2005, Novartis issued a “Dear Doctor” letter regarding Zometa and Aredia, indicating that patients on injected bisphosphonate therapy should avoid invasive dental procedures, and that a dental examination should occur before initiating intravenous bisphosphonate therapy. The letter quoted the new precaution to be placed in the product label in August 2004. Precautions

Osteonecrosis of the Jaw

Osteonecrosis of the jaw (ONJ) has been reported in patients with cancer receiving treatment regimens including bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. The majority of reported cases have been associated with dental procedures such as tooth extraction. Many had signs of local infection including osteomyelitis.

A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, corticosteroids, poor oral hygiene).While on treatment, these patients should avoid invasive

While the number may seem small when compared to the estimated 39 million oral prescriptions written in 2005, the problems still indicated a trend and may have signaled a serious problem for long term use of bisphosphonates.

“We’ve uncovered about 1,000 patients (with jaw necrosis) in the past six to nine months alone, so the magnitude of the problem is just starting to be recognized,” Kenneth Hargreaves, of the University of Texas, told the newspaper.

WHAT WAS THE FDA RESPONSE?

In August 2004, the FDA’s Office of Drug Safety issued its Postmarketing Safety Review on about four bisphosphonate drugs used to treat osteoporosis: Fosamax, Zometa, Aredia, and Actonel. The FDA report concluded that warning language about adverse events involving osteonecrosis should be added to the drugs’ labels.

On September 24, 2005, Novartis issued a “Dear Doctor” letter regarding Zometa and Aredia, indicating that patients on injected bisphosphonate therapy should avoid invasive dental procedures, and that a dental examination should occur before initiating intravenous bisphosphonate therapy. The letter quoted the new precaution to be placed in the product label in August 2004. Precautions

Osteonecrosis of the Jaw

Osteonecrosis of the jaw (ONJ) has been reported in patients with cancer receiving treatment regimens including bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. The majority of reported cases have been associated with dental procedures such as tooth extraction. Many had signs of local infection including osteomyelitis.

A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, corticosteroids, poor oral hygiene).While on treatment, these patients should avoid invasive

Osteonecrosis of the Jaw

Osteonecrosis of the jaw (ONJ) has been reported in patients with cancer receiving treatment regimens including bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. The majority of reported cases have been associated with dental procedures such as tooth extraction. Many had signs of local infection including osteomyelitis.

A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, corticosteroids, poor oral hygiene).While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

Actonel precautions changed in May 2005. Similarly, Merck changed its Fosamax precautions on July 20, 2005. The drug maker, said in a statement that in “all of our controlled clinical trials with Fosamax, which involved more than 17,000 patients, including some that were 10 years in duration, we had no reports of ONJ.”

Merck stated it received a request from the FDA to update the label in January 2005. BISPHOSPHONATE LITIGATION STATUS

A class action lawsuit filed in early April 2006 in Florida alleges that Merck failed to change the package insert or label for Fosamax in a timely manner given what was known, and when, about the apparent connection or link between Fosamax and osteonecrosis of the jaw. As of May 9, 2006, Merck reported that 15 additional suits were filed. The company has cases pending against it in Tennessee, Pennsylvania, and Florida.

The Judicial Panel on Multidistrict Litigation consolidated in the Middle District of Tennessee federal litigation over Aredia and Zometa, two drugs used in cancer treatment that allegedly cause degradation of the jaw, In re: Aredia and Zometa Products Liability Litigation, W.D. Tenn., MDL No. 1760, April 18, 2006. The panel excluded litigation over Fosamax and Actonel, reasoning that because Zometa and Aredia are intravenous drugs, they had little in common with Fosamax and Actonel, which are oral medications. Judge Todd J. Campbell presides over the MDL.

THE SCIENCE BEHIND BONE STRUCTURE & GROWTH

How are our bones structured? Bone is a physical structure shaped like a honey-comb. That is, our bones are not “solid” all the way through. Like a honeycomb, the bone is comprised of “chambers” which are occupied by living cells. These living cells, just like all cells in our bodies, require blood flow (oxygen, nutrients) to stay healthy. The bone cells, that occupy the bone matrix chamber, when mature, form a hard calcium, and other mineral, structure around them. The mature bone cells are known as osteocytes.

How does the body make new bone? In order to understand how a bisphosphonate works, one must next understand the process by which the body makes new bone and how it removes old bone. The process takes place with a third type of bone cell known as an osteoclast. Osteoclasts are cells that allow the body to resorb or take away the hard calcium structure that houses the mature and dying osteocyte.

An osteocyte cell, the mature cell inside the bone, has a normal life of 150 days. Therefore, after 150 days, the cell must be replaced with a new cell. The osteoclast cells attach to the outside of the “chamber” and soften the chamber wall, allowing the old dying osteocyte cell to escape from the boney calcium matrix and form a new osteoblast, an immature osteocyte, cell to penetrate the chamber. As the saying goes, “Out with the old and in with the new.”

The osteoblast then matures, hardens up the chamber with new calcium and minerals, and lives there for the next 150 days, when the process starts all over again.

What can go wrong? The problems occur when any of the three types of cells begin to operate out of balance with the others. For example, in the case of certain cancerous tumors, the body is stimulated into producing more osteoclast cells. This causes the softening of the “body armor” that surrounds the osteocytes – the matter that makes up the hard calcium part of our bone. When the osteoclasts soften the bone, openings in the bone matrix are created. The cancer cells use these openings to