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Fosamax Lawsuits

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 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 penetrate and metastasize into the bones.

Problems

also occur naturally with aging. Osteoporosis can occur when the body s production of osteoblasts is unable to keep up with the demand for new bone. Conditions like osteoporosis can also be caused by taking other prescription drugs, such as the birth control Depo Provera, which is known to reduce bone mass density.

Hypercalcemia is a third condition treated by bisphosphonates. It is accompanied by tumors 20 percent of the time. Essentially, in hypercalcemia, the body has too much calcium in the blood flow. To reduce this, the bisphosphonate retards the osteoclast production and the calcium simply stays in the bone matrix.

BISPHOSPHONATE FUNCTION AND EFFECT

How does a bisphosphonate work? A common misperception is that bisphosphonates cause

the body to make more bone. They do not. They simply slow down the process of removing the dead bone cells from within the matrix by inhibiting the production of osteoclast cells, or the cells that soften the bone. Thus, the body has more hard bone chambers than it would have, but it is at the cost of having fewer chambers housing healthy cells.

How does bisphosphonate cause bone necrosis? In the case of necrotic jaw bone disease, the body is left with a boney structure without new and healthy osteoblasts that are going to mature into osteocytes. Simply stated, more of the bone cells are like vacant apartments, or worse yet, apartments with a dead occupant. The

result of not having healthy bone cells is that the blood flow through the bone is then reduced which can result in pervasive bone death where all of the cells in the bone die because there is insufficient blood flow.

Is it worth the risk? In the case of cancer, taking bisphosphonate drugs may be worth the risk. But osteonecrosis of the jaw is not necessarily a foregone conclusion. Certain actions, as discussed below, can mitigate the risk. However, since there are currently no known ways of preventing certain cancer from spreading to bones, bisphosphonates provide an effective treatment. These drugs substantially reduce the risk of metastatic bone cancer.

However, in the case of osteopenia, a borderline osteoporosis

condition, or even for osteoporosis, a range of alternatives exist, from 1) changes in diet, such as ingesting more calcium; lifestyle changes, such as giving up smoking; 2) exercise, i.e. weight-bearing exercise to stimulate bone growth; and 3) other effective medications that use a different mechanism. For example, Forteo, manufactured by Eli Lilly and Co., is an injection that works by bone surfaces stimulation of osteoblastic activity. 4) Other measures can be taken to prevent the onset of osteoporosis. For example, despite other side effects, hormone replacement therapy (HRT) has been shown to help prevent osteoporosis.

ONJ ONSET

How does ONJ occur? The bisphosphonate inhibits osteoclast production.. As a result, when the osteoclast is unable to

soften the outer shell of the bone cell (the part of the bone that makes it hard), then there is no way for the new osteoblast cell to get into the boney structure to replace the dying mature osteoblast (osteocyte).

When the mature cells die in the bone they can no longer maintain the Haversian canals and the blood flow through those openings ceases. The Haversion canals consist of a central hole surrounded by rings of bony tissue arranged concentrically around the central bone canal.

When the periosteal blood flow, or blood within the bones, ends, then soft tissues around that bone and within the bone itself, which depend on that blood flow for health, also begin to die (or

fail to heal).

How long is a patient at risk after taking bisphosphonates? The half-life of bisphosphonates in the body is 10 years. The mean-time to a necrotic event is 3 years after administration/ingestion of the bisphosphonates, leading to significant latency.

Dental surgical procedures play a significant role in ONJ cases. For example, 27 percent of all necrotic jaw events related to bisphosphonates are spontaneous, meaning there was no trauma, especially including no dental procedure that would bruise the jaw bone and tissues surrounding the jaw bone and teeth. However, 73 percent of these events involved a trauma or dental procedure precipitating the necrosis.

Thus, a dental procedure may cause bone damage, cutting off sufficient blood supply due

to the osteoclast inhibition caused by the bisphosphonates. As such, instead of blood flow carrying oxygen and other nutrients needed for the tissue/bone to heal, the procedure causes bone and tissue death. In addition, it appears that bisphosphonates can cause a widening of the ligament around a tooth. When this occurs, it can be seen on an x-ray as a radiolucency between teeth. Under ordinary circumstances, a dentist would remove that tooth. If the tooth is retained, food or worse yet, bacteria can enter the space next to the tooth and cause decay or disease. However, with a patient who was on bisphosphonates, extraction may not be an option. In fact, doctors recommend against removal and simply performa root canal or other procedure to remove only the top of the tooth.

To counter this risk, three tasks may be undertaken. 1) If a patient is treated with bisphosphonates, they must have all currently required or anticipated dental procedures completed before they begin their bisphosphonates treatment. They must then wait at least one month after such procedures before beginning their course of bisphosphonates. 2) While taking bisphosphonate drugs, patients must tend to their dental hygiene. 3) A root canal, instead of tooth extraction lessens the amount of trauma.

Why the Jaw? The jaw is vascular, which may account for a higher quantity of bisphosphonates reaching that bone. In addition, its high need for blood flow may explain the significant

impact on the jaw when blood flow is diminished.

What can be done once ONJ has occurred? The key is to prevent ONJ. Surgery cannot reverse the damage for a patient who was treated with bisphosphonates, and a surgical procedure would tend to worsen the situation. On the other hand, a doctor might simply remove the necrotic tissue and bone and stimulate the tissues to promote the tissue or bone to grow back for a patient who did not take bisphosphonates.

HOW TO SCREEN FOR A BISPHOSPHONATE CASE To determine whether a potential bisphosphonate case exists:

1) Consider the reason why the bisphosphonate was prescribed. If the client has cancer and was prescribed a bisphosphonate to prevent metastatic

cancer, you may question whether a plaintiff or her physician would choose to heed a warning about the potential for ONJ. Since the adverse event is a class effect, a reasonable alternative may have been missing.

A countervailing consideration is that a warning could have caused the plaintiff s physician to assure that all dental work needed was completed before the bisphosphonate therapy began and that the plaintiff was carefully instructed on good dental care and the increased risks associated with poor dental hygiene while on bisphosphonates.

2) You must determine for each individual patient whether the dental problem or procedure that lead to the ONJ could have been avoided by good dental hygiene or could have been performed before

the initiation of treatment.

3) Consider the length of time that the plaintiff was on the treatment before developing ONJ. Due to the mechanism of action (preventing bone take-away), bisphosphonates will need time to set up the structures that are susceptible to infection leading to ONJ.

4) Consider the drug regimen, since many chemotherapy drugs can lead to a weakened immune system, making infection more likely.

5) In the non-cancer patient, you must consider the length of use. You may be unable to sustain a case where the exposure to the drug was less than three months. Actually, the longer the exposure, the better is the case. If the plaintiff has been on the drug for a substantial period of

time, the fact that the patient went off the drug and then developed ONJ does not mean that a case does not exist. Bisphosphonates have a long half life. For example, Fosamax has a half-life of 10 years. In cases of cancer patients with injectable bisphosphonates, the warning must have a meaning, so the dental procedure should be one that could have been prevented by adequate precautions or avoided altogether.

6) You must consider the degree of osteoporosis for which the client was prescribed a bisphosphonate. If the client had a very high fracture risk, they may have decided on the Fosamax anyway, because severe osteoporotic fractures are associated with a high mortality, quoted as high as 20 percent. On

the other hand, if the use of a bisphosphonate was merely preventative on a patient with osteopenia, the case may be stronger.

7) You must also consider when the bisphosphonate was prescribed in relation to the warnings. If first prescribed after the change in the warnings, there is very little chance a case could be sustained. If problems first arise after the warning dates, a viable case may still exist, because earlier warnings may have given the patient and her physician a choice on whether to use the drug.

Bisphosphonates may be another example of a drug marketed as a near panacea for the scourge of osteoporosis and a great aid in the treatment of cancer, but it lacks adequate

after-market monitoring to protect the public from the inevitable adverse events. Presently, lawyers who are willing to take on Big Pharma when drugs go bad constitute the only real protection for the public. Hopefully, in the future, drug companies will honor their ethical responsibility to assure the drugs safety before initiating the huge sales push that accompanies the launch of new drugs.

In addition, a stronger FDA can help prevent the unnecessary injuries and deaths associated with prescription drugs which in the last decade are sold as any other consumer product instead of as their status as specialty medical products.

Sources

The press release can be seen in its entirety at http://www.northshorelij.com/body.cfm?id=204&action=detail&ref=682

Ruggiero SL, Mehrotra

B, Rosenberg TJ, et al: Osteonecrosis of the jaws associated with the use of bisphosphonates: A review of 63 cases. J Oral Maxillofac Surg 62:527-534, 2004

Marx RE: Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: A growing epidemic. J Oral Maxillofac Surg 61:1115-1117, 2003

YOU: The Owner’s Manual: An Insider’s Guide to the Body that Will Make You Healthier and Younger, by Mehmet Oz, Michael F. Roizen. (Page 107). ISBN: 0060765313 - HarperCollins

http://www.fda.gov/medwatch/SAFETY/2004/DepoProvera_Label.pdf .

http://www.emedicine.com/emerg/topic260.htm.

http://www.drugs.com/PDR/Forteo_Injection.html.

http://www.nlm.nih.gov/medlineplus/ency/article/007111.htm.

Gray s Anatomy. http://education.yahoo.com/reference/gray/subjects/subject?id=18.

J. Oral and Maxillofacial Surg. 63:1567-1575, 2005; JADA Vol 136 December 2005 1658-1669 & 1669-1675 & 1675-1682

J. Oral and Maxillofacial Surg. 2003: 61(9):1115-7

J. Oral and Maxillofacial Surg. 2004: 62(5):527-34

J. Oral

and Maxillofacial Surg. 2005: 63(5):682-9

Ibid.

Michael Monheit is a member of Anapol, Schwartz, Weiss, Cohan, Feldman & Smalley, P.C., 1900 Delancey Place, Philadelphia, PA 19103 [mailto:michael@monheit.com] michael@monheit.com; [mailto:mmonheit@anapolschwartz.com] mmonheit@anapolschwartz.com.

Tracy A. Finken Anapols, Schwartz, Weiss, Cohan, Feldman & Smalley, P.C., Philadelphia, PA, Phone: 215.735-0773, [mailto:tfinken@anapolschwartz.com] tfinken@anapolschwartz.com.

Contact them online about your [http://www.anapolschwartz.com/practices/fosamax/] Fosamax Lawsuit.