Presented in Chicago July 2007

Fosamax (Bisphosphonates)

By: Michael Monheit, Esq.

Anapol, Schwartz, Weiss, Cohan Feldman, & Smalley, P.C.

Mmonheit@anapolschwartz.com

When was this problem first identified?

• This is not a “new” disease.• In the 1800’s a disease known as “Phossy

Jaw” was seen in workers in the matchstick making business

• The problem was caused by exposure to high levels of white phosphorus

• It resulted in necrotic infections in the jaw bone

What is BRONJ?

• BRONJ = Bisphosphonate Related Osteonecrosis Of The Jaw

• This is a new etiology for a long-known disease. (First identified in 2003)

• This problem is now seen as a unique etiology of bone destruction. Damage to the Maxilla and/or Mandible(more common).

BRONJ on the Rise

• Growing number of patients exhibiting symptoms of BRONJ

• Characterized by exposed, necrotic bone in the maxillofacial region

• Investigation revealed link between IV and oral bisphosphonate drug treatment

What do oral surgeons know about BRONJ??

• The American Association of Oral & Maxillofacial Surgery (AAOMS) has issued a statement on this problem. (JOMS: 65:369-376, 2007)

• Recent Papers Have Shown That Jaw Osteonecrosis Of Aseptic Etiology Is Associated With The Use Of Bisphosphonates (Bibloigraphy Available on Request)

What does the ADA say about BRONJ?

• Routine dental treatment should not be withheld solely on the basis of oral bisphosphonate therapy

• Patients should be encouraged to maintain optimum oral hygiene and regular dental care

• Before undergoing any invasive (surgical) procedure, the patient should be informed of the very low risk for BRONJ, but that the vast majority of patients do not have any problems

See: (JADA 2006;137(8):1144-50)

What are Bisphophonates used for?

Are Used To Treat Several Disease Entities– Primary Osteoporosis

• Phase 1: trabecular bone resorption due to estrogen deficiency. Peaks after 4-8 years (women only)

• Phase 2: persistent, slower loss of both trabecular and cortical bone which is mainly due to decreased bone formation (men and women)

– Secondary Osteoporosis: Long term steroid use, Cushing’s disease, anorexia nervosa, athletic amenorrhea, HPT, cystic fibrosis, inflammatory bowel disease, rheumatoid arthritis

– Cancer Patients: To protect from bone metastases of certain cancers

What drugs are involved?

DRUG RELATIVE POTENCY

• Etidronate (Didronel) 1• Tiludronate (Skelide) 10• Pamidronate (Aredia) 100• Alendronate (Fosamax) 1,000• Risedronate (Actonel) 10,000• Ibandronate (Boniva) 10,000• Zolendronic acid (Zometa) >100,000

How big of a market is this?

Surgeon General Report (2004)– 40% of American women > 50 yo.

• Will experience an osteoporotic fracture

– 13% of men 50 yo.– By 2020 it is estimated that 50% of all

Americans over the age of 50 will be at risk of developing osteoporosis

– Direct cost expenditures for 1.3 million fractures per yr = $14 billion +

How does a Biphosphonate treat Osteoporosis?

• Osteoporosis occurs when there is an imbalance between bone formation and bone resorption– It is a disease with low bone mass and

deteriorated bone structure– It increases bone fragility and risk of fracture

• Bisphosphonates treat this imbalance by reducing bone resorption.

How is bone formed & replaced?

• Osteoblast = New bone cells. When they enter the bone matrix, they become Osteocytes.

• Osteoclasts = Cells that soften bone to allow the old Osteocyte out of the bone and the new Osteoblast into the bone

• Bisphosponates “harden” the bone by holding retarding Osteoclasts. They reduce bone turnover by:

– Killing Osteoclasts (Hughes et al., Rogers et al.)– Inhibition of osteoclast recruitment on the bone surface (Rodan et al., Vitte et al.)– Inhibition of osteoclastic activity on the bone surface (Rodan et al., Strewler)

Bone Remodeling Process

• Osteoblast pre-cursor enters bone Become Osteoblast. Matures into an Ostecyte Live 50-80 days Osteoclast uses acid to soften bone Dead Osteocyte cells escapes bone structure New Osteoblast enters bone etc.

What Triggers ONJ?

• Radiation therapy to tumors of head and neck creates hard and soft tissue hypoxia, which impedes healing and triggers bone necrosis

• Bacterial infection (primary, or secondary to dental work) can result in osteomylitis

• Bisphosphonates (aseptic)– Related to method of administration: IV v. PO

– Related to the duration of administration

What are causes of BRONJ?

• Can Be Related To Dental Treatment – About 60% of patients had some form of dentoalveolar (tooth and bone

surrounding it) surgery

• Can Be Related To Dental Pathology• Can Be Spontaneous With Dental Etiology• Can Be Related To Denture Irritation Or Wear• Can Be Related To Local Trauma• Can also have unknown etiology

– About 25% of cases occur without an identifiable cause

What are the problems associated with ONJ?

• Very painful and serious sequelae.• Very difficult to treat• Typical presentation is that of an area of

exposed bone which may be asymptomatic, but which can become infected secondarily and then become painful.

• Tissue will not heal over the “dead” bone.

How Does BRONJ Present?• American Dental Association (ADA) —Typical clinical

presentation includes pain, soft-tissue swelling and infection, loosening of teeth, drainage, and exposed bone

• American Society for Bone and Mineral Research (ASBMR) — Typically appears as an area of exposed alveolar bone in the mandible or the maxilla. May or may not be painful. May or may not be associated with infection or local trauma. Most often develops after a recent tooth extraction or oral contusion/abrasion

• American Association of Oral and Maxillofacial Surgeons (AAOMS) —Exposed bone in the maxillofacial region that has persisted for >8 wks in the presence of current or previous treatment with bisphosphonates and absence of radiation treatment to the jaws

Stage 1 ONJ

• Characterized by exposed bone that is asymptomatic with no evidence of significant soft tissue infection

Stage 2 ONJ

• Exposed bone associated with pain, soft tissue and/or bone infection

Stage 3 ONJ

• Pathologic fracture• Exposed bone

associated with soft tissue infection or pain that is not manageable with antibiotics due to the large volume of necrotic bone.

Long Term Implications

• Incorporated into the skeleton without being degraded, thus they are remarkably persistent drug. Estimated half-life of alendronate (Fosamax) is up to 12 years!

• Because of the long half-life, recovery of normal osteoclast function after discontinuance is gradual and prolonged

• Prolonged use of bisphosphonates may suppress bone turnover sufficiently to cause microdamage and hypodynamic (brittle) bone with decreased biomechanical competence

How do you treat BRONJ?

• Antibacterial mouthwash (Chlorhexidine)

• Superficial debridement only

• Pain control

• Antibiotics if infection is present

• There is no evidence that discontinuation of bisphosphonates improves outcome

About the MDLand Fosamax Lawsuits

• MDL-1789 (see: http://www.levinlaw.com/PracticeAreas/FosamaxMDL1789.mht)

– Also MDL 1760 in M.D. TN for Aredia & Zometa

• Litigation Caption: In re Fosamax Products Liability Litigation

• District: Southern District of New York• Litigation Transfer Date: 08/16/06• Transferee Judge: Hon. John F. Keenan• Web Site:

http://www.jpml.uscourts.gov/Pending_MDLs/Products_Liability/MDL-1789/mdl-1789.html

Presented in Chicago July 2007

Fosamax (Bisphosphonates)

By: Michael Monheit, Esq.

215-840-6573

Philadelphia, Pennsylvania Lawyers

Anapol, Schwartz, Weiss, Cohan Feldman, & Smalley, P.C.

Mmonheit@AnapolSchwartz.com