NEWS - Legal action on jaw osteonecrosis from bisphosphonates

[Guest guest]

Legal action on jaw osteonecrosis from bisphosphonates

Rheumawire

June 3, 2005

Zosia Chustecka

Knoxville, TN - In the US, a class-action suit involving 30 patients with

jaw osteonecrosis linked to the intravenous bisphosphonate pamidronate

(Aredia, Novartis) has been filed against the manufacturer. Most

participants were cancer patients, but two of the 30 were using the drug for

severe osteoporosis, civil litigation specialist Threadgill (Knoxville,

TN) tells rheumawire. He is also preparing a class-action suit against Merck

& Co on behalf of patients who developed jaw osteonecrosis after using the

company's oral product, alendronate (Fosamax), which has been associated

with fewer cases but symptoms that are just as severe.

" Jaw osteonecrosis can be catastrophic, " Threadgill says. " Two of the

patients involved have lost their complete lower jawbone, have no teeth, and

have no possibility of implants or even wearing a denture because of bone

damage. " In two other cases, the osteonecrosis has spread to the sinus and

facial bones and has led to disfiguring surgery. The damage can be both

severe and disabling and is among the worst drug-induced damage he has ever

come across, but he also notes that the severity of the side effect varies

from one patient to another.

Threadgill posted an advertisement on the internet calling for patients who

experienced complications from the bisphosphonates and says he has received

calls from Europe, Australia, and the US. The firm estimates that there may

be some 300 000 patients affected worldwide. Threadgill explains that this

is based on the 2.5 million patients that Novartis estimates have taken

pamidronate and another IV bisphosphonate, zolendronate (Zometa), and an

estimate from an informal web-based survey of cancer patients that 12% to

15% of patients may be affected by this side effect. As previously reported

by rheumawire, this is likely to be an overestimate. This and other

estimates of incidence were discussed at an FDA hearing into jaw

osteonecrosis associated with IV bisphosphonates in cancer patients, held in

March 2005 [1]. A review of cancer-patient case histories suggests the

incidence is around 1.9%. Novartis suggests the incidence is around 0.03%,

based on the number of patients using the drugs and the 875 reports of jaw

osteonecrosis it had received before March 2005; however, a review of its

clinical-trial data suggests an incidence of around 0.15%.

The FDA has issued two warnings about osteonecrosis associated with

bisphosphonates, the latest just last month, and the Australian Adverse Drug

Reactions Advisory Committee (ADRAC) has recently issued a warning in which

it says it has received nine reports of this side effect [2].

" Just the tip of the iceberg "

The cases reported so far may be " just the tip of the iceberg, " says oral

and maxillofacial pathologist Dr Hellstein (University of Iowa, Iowa

City) [3]. He predicts that the problem will be of " rare " clinical concern

to the individual using oral bisphosphonates, but overall numbers could rise

because these drugs are used so widely by the population as whole. He points

out that an estimated 27 million prescriptions were written for US

osteoporosis patients in 2004, whereas only about 300 000 to 500 000 US

cancer patients use intravenous bisphosphonates each year. Hellstein tells

rheumawire that his impression is that the complication occurs much less

frequently with the oral products used in osteoporosis than the intravenous

drugs used in cancer patients (which are also used at a much higher relative

dose). Of all the cases of oral osteonecrosis seen so far, about 90% to 95%

are linked to infused drugs and the remaining 5% to 10% to oral drugs. He

bases this estimate on current literature and an informal poll of oral

pathologists discussing anecdotal cases at a recent meeting of the American

Association of Oral and Maxillofacial Pathology.

The good news about this complication is that it's easy to spot: " It's

pretty obvious . . . exposed bone in the mouth is pretty uncommon, "

Hellstein says. " But the bad news is that the lesions vary from small to

large and take months or years to heal. Topical antibiotics, such as

chlorhexidine, and minimal or no surgery are the mainstays of therapy.

Currently, prevention is key. Patients who are to be started on infused

bisphosphonates should undergo exams and dental treatments similar to those

recommended for hip replacements or organ transplant. For the osteoporosis

patient, good oral hygiene and regular dental care will go a long way in

reducing severe periodontitis and dental caries. These simple steps will

decrease the need for dental extractions and thus decrease the already-low

risks associated with oral bisphosphonates. The key for the patient will be

knowledge and informed consent. " Hellstein believes that one of the most

worrying aspects is that the bisphosphonates stay in the bone for a very

long timesome studies suggest bisphosphonates linger in the bone for up to

10 years after prolonged use, so the risk may remain even after the drug is

stopped. " In patients with exposed bone, it seems prudent to discontinue the

oral bisphosphonate until the lesion resolves. "

His advice to rheumatologists who have patients on bisphosphonates is to be

aware of the complication and to refer any potential problems or concerns to

an oral surgeon, preferably one at an institution that has experience with

this issue, rather than to general-practice dentists. He is also working on

a position paper to advise how to proceed with dental work in a patient who

is taking an oral bisphosphonate for osteoporosis and how management would

differ from patients not on these drugs.

It's important to keep the concern in perspective, Hellstein says: " We don't

want people to stop taking bisphosphonates for osteoporosis. The morbidity

and mortality from hip fracture at age 70 is going to be far more common

than the risk of jaw osteonecrosis. The current risk of osteonecrosis from

oral bisphosphonates is very low perhaps on the order of one in 100 000 to 1

000 000, or less. "

But is it a " real phenomenon " ?

However, an osteoporosis expert with extensive experience of bisphosphonates

questions whether this is " a real phenomenon. " Prof Rick Adachi (McMaster

University, Hamilton, ON) says he has never seen osteonecrosis of the jaw,

adding, " I don't believe that this is a significant problem in patients with

osteoporosis. "

Adachi and colleagues run two large databases (CANDOO and CAMoS), each with

more than 10 000 patients with osteoporosis being followed for response to

therapy, examination of risk factors, etc. He tells rheumawire: " I have had

between 15 and 20 years of experience with bisphosphonates and have followed

around 5000 patients for as many as 15 years. I have never seen

osteonecrosis of the jaw. If it is a real entity, the number of people who

get it must be very small compared with the number who have benefited from

therapy. Putting this in perspective, we know that the more potent

bisphosphonates reduce the risk of hip fracture by 30% to 50%, and that

those who do fracture their hip suffer tremendous morbidity, with

hospitalization, surgery, nursing-home care, and death rates of 20% to 30%.

Compare this with the 1 in 10 000 who may, and I emphasize may, suffer from

osteonecrosis of the jaw. At this stage, we don't know if this is a real

phenomenon. While there may be an association, I believe that it is really

important to put it into context. "

Sources

1. Department of Health and Human Services. Food and Drug

Administration. Center for Drug Evaluation and Research. Oncologic Drugs

Advisory Committee. March 4, 2005. Available at:

http://www.myeloma.org/pdfs/ODAC2005-4095T2.pdf.

2. Australia Therapeutic Goods Administration. Australian

Adverse Drug Reactions Bulletin 2005; 24 (1): February. Available at:

http://www.tga.gov.au/adr/aadrb/aadr0502.htm#3

3. Hellstein JW and Marke CL. Bisphosphonate osteonecrosis

(bis-phossy jaw): is this phossy jaw of the 21st century? J Oral Maxillofac

Surg 2005: 63:682-690.

Not an MD

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org