IV or Long Term Oral Caution Re Biisphosphonates

[Guest guest]

Date: 2004-12-30

Doctors Link Common Chemotherapy Drug To Jawbone Necrosis

NEW HYDE PARK, NY -- Doctors at Long Island Jewish (LIJ) Medical

Center recently discovered a link between a common chemotherapy drug

and a serious bone disease called osteonecrosis of the jaw (ONJ). The

discovery, published in the Journal of Oral and Maxillofacial

Surgeons, prompted both the US Food and Drug Administration (FDA) and

Novartis, the manufacturer of bisphosphonates used in cancer

chemotherapy, to issue warnings earlier this fall to physicians and

dentists about the risk for this potential adverse effect. ONJ is a

condition in which the bone tissue in the jaw fails to heal after

minor trauma such as a tooth extraction, causing the bone to be

exposed. The exposure can eventually lead to infection and fracture

and may require long-term antibiotic therapy or surgery to remove the

dying bone tissue.

The chief of the Division of Oral and Maxillofacial Surgery at LIJ,

Salvatore Ruggiero, DMD, MD, and his staff reported that they were

struck by a cluster of cancer patients with necrotic lesions in the

jaw -- a condition they rarely saw, in only about one to two patients

a year. When they launched a study of patients' charts, they found

that 63 patients diagnosed with this condition over a three-year

period shared only one common clinical feature: they had all received

long-term bisphosphonate therapy.

Bisphosphonates are commonly used in tablet form to prevent and treat

osteoporosis in post-menopausal women. Stronger forms are widely used

in the management of advanced cancers that have metastasized to the

bone, where the disease often causes bone pain and possibly even

fractures. Several cancers can involve or metastasize to the bone,

including lung, breast, prostate, multiple myeloma and others. In

cancer chemotherapy, the drugs are given intravenously, and usually

for long periods of time.

In their study, Dr. Ruggiero and his staff teamed up with Bhoomi

Mehrotra, MD, in the Division of Hematology-Oncology at LIJ, and

doctors in the Oral-Maxillofacial Surgery Division at the University

of land Medical Center. Of the 63 patients diagnosed with ONJ

between February 2001 and November 2003 at their centers, 56 were

cancer patients who had received infusions of bisphosphonates for at

least a year and seven were non-cancer patients who had been

receiving long-term oral therapy for osteoporosis. The patients

developed ONJ after normal bone trauma, such as a tooth extraction,

while receiving bisphosphonate therapy. Rather than healing, the bone

began to die, and the majority of patients required surgery to remove

the diseased bone.

In the FDA MedWatch and Novartis alerts issued in late September,

oncologists and dentists were advised of the addition of

osteonecrosis of the jaw to the " Precautions " and " Adverse Reactions "

sections on the labeling of injectable bisphosphonates, describing

the spontaneous reports of the condition being found mostly in cancer

patients. The alerts also recommend a dental examination with

appropriate preventive dentistry in patients with risk factors such

as cancer, chemotherapy, corticosteroids and poor oral hygiene prior

to initiating treatment with bisphosphonates.

" Monitoring the dental health of patients on bisphosphonates is key

because an early diagnosis may reduce the complications resulting

from advanced destruction of the jaw bone, " said Dr. Ruggiero. " Since

our paper was published and dentists became aware of the connection,

many more patients with the condition have been identified, even in

our own center. Prevention and early detection are so important to

preserving the jaw bone in these individuals. " Individuals should

attempt to avoid tooth extractions and other major dental work while

on the drugs.

Bisphosphonates block the work of bone cells called osteoclasts, one

of two important types of bone cells that are involved in the

continuous process of bone remodeling in a delicate balancing act.

During this process, osteoblasts -- " the good guys " -- put calcium in

the matrix of the bone and make bone stronger, and osteoclasts --

" the bad guys " -- take calcium away, diminishing the internal

strength of the bone. Bone remodeling is like a necessary game of tug-

of-war between the goods guys and the bad. Bone mass and mineral

content constantly adjust throughout the life cycle to support the

places on the skeleton where the most outside force occurs.

Novartis's Aredia® (pamidronate disodium) and Zometa® (zoledronic

acid) injections are the two intravenous bisphophosphonates used in

chemotherapy regimens. Novartis changed their labeling in August.

Merck's Fosamax® (alendronate) and Procter and Gamble

Pharmaceuticals's Actonel® (risedronate sodium) are the most commonly

used oral bisphosphonates, which are only indicated for osteoporosis.

Labeling for the oral forms has not been changed. " The oral form is

much less potent than the intravenous form and appears to be

substantially less likely to cause the problem, " said Dr. Ruggiero.