NEWS - More than 50 cases of jaw osteonecrosis with Fosamax (alendronate)

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More than 50 cases of jaw osteonecrosis with alendronate

Rheumawire

17 June 2005

Zosia Chustecka

Miami, FL - The adverse event of jaw osteonecrosisreported with the use of

intravenous bisphosphonates in cancer patientshas also been seen with the

use of oral bisphosphonates in osteoporosis patients. Dr Marx (chief

of the division of oral and maxillofacial surgery, Miami University, FL)

tells rheumawire that he has personally seen five cases associated with

alendronate (Fosamax, Merck & Co) but has documented more than 50 cases

associated with alendronate reported by fellow oral surgeons and dental

colleagues. He is also aware of one case associated with risedronate

(Actonel, Procter & Gamble).

" This is definitely a side effect of the bisphosphonates, there's no doubt

about it, " Marx told rheumawire in an interview. " It's rare, occurring in

perhaps one out of 10 000 patients, " he comments. Also, it occurs some time

into the therapy, after patients have been taking alendronate for about two

to three years. Of the 50+ cases with alendronate that he's aware of, about

60% have developed after a dental procedure, such as a tooth extraction, but

the other 40% of cases occurred spontaneously.

" Rheumatologists and all physicians who prescribe bisphosphonates should be

aware of this side effect and should be on the lookout for it, making sure

that they remember to check inside these patients' mouths on a regular

basis, " Marx says. The best strategy is preventionas 60% of cases appear to

follow a dental procedure, it would be prudent to send patients for these

procedures before they start on a course of bisphosphonate therapy and to

encourage thorough dental hygiene at all times. Once on the drug, invasive

dental procedures should be avoided, even for some time after stopping

therapy, as the effects of these drugs in the bone are very long

lastingalendronate has a half-life of more than 10 years, he notes.

However, Marx adds that the potential risk must be kept in perspective and

must always be weighed against the benefit of these drugs. For instance,

when used in the treatment of bone-cancer metastases, bisphosphonates have

dramatically extended life and reduced skeletal complications and pain, thus

improving quality of life. In osteoporosis, the bisphosphonates have been

shown to increase bone-mineral density and significantly reduce the risk of

fractures.

Postmarketing reports

As previously reported by rheumawire, jaw osteonecrosis has recently been

added as a warning to the prescribing information for two intravenous

bisphosphonates used in cancer patients, zoledronate (Zometa, Novartis) and

pamidronate (Aredia, Novartis). At an FDA hearing on this subject in March

2005, Novartis said it had 875 reports of jaw osteonecrosis associated with

the two intravenous products.

At present, there is no mention of jaw osteonecrosis on the labeling of any

oral products. Merck says it is " in discussions with regulatory authorities

on this issue. " As of March 2005, the company had received between 50 and

100 reports of jaw osteonecrosis associated with alendronate, spokesperson

Heinley told rheumawire. These are all postmarketing reports, where

there is uncertainty over causality, he pointed out. The company saw no

cases of jaw osteonecrosis during preclinical studies, in which alendronate

was used at far higher doses than are approved for osteoporosis, and also no

cases were seen in controlled clinical trials, which involved more than 17

000 patients. Alendronate has been on the market for 10 years now, during

which time total exposure to the drug is estimated at around 2 million

patient-years, he added.

Marx was the first to report the side effect of jaw osteonecrosis with

zoledronate and pamidronate, in August 2003 [1]. With colleagues, he has

recently written a review of 119 patients, most of whom were taking these

intravenous agents, but three of whom were taking oral alendronate for

osteoporosis [2]. All were taking 10-mg alendronate daily, one patient for

six years, another for three years, and the third for two years; the mean

time to bone exposure associated with alendronate was three years. Marx et

al comment that a blinded study to prove causality is not possible, but all

three drugszoledronate, pamidronate, and, more rarely, alendronatehave shown

a " direct correlation that cannot be ignored. "

Side effect stems from mechanism of action

The adverse event stems from the mechanism of action of these drugs, Marx

contends. The bisphosphonates work by preventing the resorption of old

bonethey are toxic to the osteoclasts, he notes. This leads to an imbalance

in the normal order of bone turnover, where the osteoblasts build new bone

and the osteoclasts resorb the old bone on a continuous basis; this

dissolving/reforming of bone takes place at a rate of 0.7% per day, so that

within 142 days the entire skeleton is replaced, he points out.

In conditions where the bone is fragilefor instance, in osteoporosisthe

imbalance produced by the bisphosphonates is beneficial: stopping the

resorption of old bone while not affecting the formation of new bone leads

overall to a strengthening of the bone. However, in certain cases, as has

happened with these jaw-osteonecrosis patients, preventing the resorption of

old bone can produce a problem, as the old bone builds up and gets older and

eventually dies. In their review, Marx and colleagues explain that if " the

mineral matrix is not resorbed by the osteoclasts . . . the osteon becomes

acellular and necrotic. The small capillaries within the bone become

involuted, and the bone becomes avascular. A spontaneous breakdown of the

overlying mucosa, some form of injury, or an invasive surgery to the jaw

usually causes this necrotic bone to become exposed, and then it fails to

heal. "

But why is it seen only in the jaws? Marx suggests it's because bone in the

jaw has a faster turnover than bone elsewhere in the body, both because it

is in constant use from activities such as talking and chewing and also

because of the presence of teeth, which mandates daily bone remodeling at

the periodontal ligament. Also, jawbones have a greater blood supply, and

both of these factors lead to bisphosphonates becoming highly concentrated

in the jaw. This anatomic concentration of the drug, when coupled with

chronic invasive dental diseases/treatments and the thin mucosa over the

bone, " causes the condition to be manifested exclusively in the jaws, " Marx

and colleagues write.

Support for this hypothesis comes from an understanding of the disease

osteopetrosis, they comment. This inherited autosomal-dominant condition is

characterized by the loss of osteoclasts. " These unfortunate patients

develop a clinical picture identical to that of bisphosphonate-induced

exposed bone, " Marx et al note. In these patients, the exposed avascular

bone occurs almost exclusively in the jaws, at times spontaneously but

usually precipitated by an invasive dental procedure, and the exposed bone

does not resolve. In both cases, the osteonecrosis is the end product of the

loss of osteoclastic bone remodeling and renewal, the authors write.

Sources

1. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa)

induced avascular necrosis of the jaws: a growing epidemic. J Oral

Maxillofac Surg 2003; 61:115-117.

2. Marx RE, Sawatari Y, Fortin M, Broumand V.

Bisphosphonate-induced exposed bone (osteopetrosis) of the jaws: risk

factors, recognition, prevention, and treatment. J Oral Maxillofac Surg; in

press.

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