NEWS - Bisphosphonates and jaw osteonecrosis

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Bisphosphonates and jaw osteonecrosis

Rheumawire

May 20, 2005

Zosia Chustecka

Iowa City, IA - As the FDA issues another warning about jaw osteonecrosis

associated with the use of 2 injectable bisphosphonates used in cancer

patients, an oral surgeon warns that these cases may be " only the tip of the

iceberg " and says that, because they are so widely used, " even oral

bisphosphonate may yet prove to be of clinical concern [1]. " The warning is

issued by Dr Hellstein (clinical professor of oral pathology,

University of Iowa, Iowa City), in the May 2005 issue of the Journal of Oral

and Maxillofacial Surgery and publicized in a press release issued by the

American Association of Oral and Maxillofacial Surgeons.

This concern is echoed by osteoporosis expert Prof Gordon Strewler (Beth

Israel Deaconess Hospital, Boston, MA), who says, " We may be on the leading

edge of a wave of cases. " He tells rheumawire that more than 800 cases have

now been reported to the FDA and says, " I certainly do not think this issue

is trivial. . . . We may have to rethink the use of high-dose

bisphosphonates in cancermainly multiple myeloma and breast cancer with bone

metastases. The dose used orally in osteoporosis is much lower, but there

have been a few cases reported on alendronate and risedronate. " He also

emphasizes that the effect of these drugs persists even after the patient

stops treatment: " They are not cleared from the bone for years. "

However, Dr Watts (Bone Health and Osteoporosis Center, University of

Cincinnati, OH) tells rheumawire: " I have not seen any osteonecrosis of the

jaw in my patients with osteoporosis, nor have any of the colleagues whom I

have spoken with about it. I doubt that the risk is particularly great in

patients being treated for osteoporosis, but 'better safe than sorry' would

apply to patients who have ongoing dental problems. "

Warning issued for injectable products

The warning from the FDA has been issued in conjunction with Novartis about

its 2 injectable products, pamidronate (Aredia) and zoledronic acid

(Zometa), both of which are used in cancer patients for the treatment of

hypercalcemia of malignancy and for bone metastases, mainly in patients with

multiple myeloma and breast cancer but also in some other solid tumors.

However, zoledronic acid (as Aclasta, Novartis) is also in late clinical

trials for osteoporosis, for which it is thought to have huge potential, as

it may be effective with only 1 injection annually; it is also in clinical

trials in Paget's disease and rheumatoid arthritis (RA).

The latest warning, issued earlier this month, is directed at dental health

professionals and recommends that cancer patients receive a dental

examination before starting intravenous treatment with either of these drugs

and avoid invasive dental procedures while on the treatment [2]. An earlier

warning and a " Dear doctor " letter, issued in September 2004, alerted all

prescribers to reports of jaw osteonecrosis in patients taking these drugs

[3]; at that stage, Novartis said it was aware of 500 cases. There had also

been an earlier update on the product labels in August 2003.

The issue of jaw osteonecrosis associated with pamidronate and zoledronic

acid was also discussed at a meeting of the FDA Oncologic Drugs Advisory

Committee on March 4, 2005 [4]. FDA official Dr Pazdur asked the

meeting to focus only on that issue; although there have been anecdotal

reports of jaw osteonecrosis with oral bisphosphonates used in osteoporosis,

there are much fewer data on this, he said, and " the risk-benefit

considerations are different for people with malignancy compared with people

being treated for a benign bone disease. "

First spotted by oral surgeons

The complication was first spotted by oral surgeons. Dr Marx (Miami,

FL) reported a series of 36 patients in September 2003 [5]. All but 1 of

these patients were on pamidronate, zoledronate, or both for the indication

of hypercalcemia related to multiple myeloma or metastatic breast cancer; 1

patient was reportedly taking the drug for osteoporosis. Most patients

presented with painful exposed avascular bone in the mandible, the maxilla,

or both; in most of the patients (28/36, 77.7%) it followed removal of a

painful tooth, but in 8 patients it developed spontaneously. Dr Salvatore

Ruggierro and colleagues (Long Island Jewish Medical Center, New Hyde Park,

NY) reported a series of 63 cases last year [6]. Most of these patients were

taking pamidronate or zoledronate and had multiple myeloma (28 patients),

breast cancer (20 patients), or other cancers, but there were also 7

patients being treated for osteoporosis5 patients taking oral alendronate, 1

patient on oral risedronate, and 1 patient on oral alendronate as well as

zoledronic acid. These 7 patients had no of history malignant disease or

chemotherapy exposure, the researchers note.

" Typical presentation is a nonhealing tooth-extraction socket or exposed

jawbone, both of which appear to be refractory to conservative debridement

and antibiotic therapy, " Ruggierro et al comment. Typical presenting

symptoms were pain and exposed bone at the site of a previous tooth

extraction, but 9 of the 63 patients (14%) had no history of a recent

dentoalveolar procedure and nevertheless presented with spontaneous exposure

and necrosis of the alveolar bone. In addition, 6 patients had radiographic

signs of osteolysis before teeth were removed, which suggests involvement of

the alveolar bone before extraction. Ruggierro et al also reported that

cessation of bisphosphonate treatment did not have a major impact: 5

patients had persistent bone necrosis and even developed new regions of

exposed bone, despite being removed from bisphosphonate therapy by their

oncologists.

These reports prompted Dr Durie (Cedars-Sinai Outpatients Cancer

Center, Los Angeles, CA), a cofounder of the International Myeloma

Foundation (IMF) patient advocacy group, to conduct a survey, recruiting a

total of 1203 patients via cancer websites and email lists. Durie reported

the findings at the American Society of Hematology in December 2004 and has

posted the presentation on the IMF website [7]. Of 904 patients with myeloma

who responded, 62 reported jaw osteonecrosis and 54 reported " suspicious

findings " suggesting osteonecrosis, such as bone erosions, bone spurs, or

exposed bone in the jaw. Of 299 with breast cancer who responded, 13

reported osteonecrosis and 23 reported suspicious findings.

Commenting on this survey to rheumawire, Strewler notes that the results are

preliminary, the responses were anonymous, and there was no follow-up to

confirm diagnosis. " The overall incidence is strikingly high in the

respondents to the survey, " but he adds that symptomatic patients were more

likely to respond, and so there are reasons to doubt this frequency data.

But he also notes that the data show a sharply rising incidence after months

of treatment with bisphosphonates and no relationship to other drugs being

used in treatment.

When he was presenting results from the survey at the FDA Advisory meeting

in March, Durie commented on the time frame involved. The average length of

time patients had taken zoledronic acid before reporting osteonecrosis was

18 months (although some cases were seen after 6 and 12 months), and the

average length of time with pamidronate was 6 years. " There is a coincidence

of the time frames related to the time since these drugs have been on the

marketplace, " he commented. Zoledronic acid was approved for hypercalcemia

of malignancy in August 2001 and had a broad bone-metastases indication

added in February 2002; pamidronate was approved by the FDA for use in

hypercalcemia of malignancy in 1991, multiple myeloma in 1995, and

osteolytic bone metastases in breast cancer in 1996.

At the FDA hearing, Novartis said that its pamidronate product, Aredia, had

been used by 1.9 million patients since 1991 but added that it was no longer

used much in the US, having been replaced by generic pamidronate. The

company said 1 million patients have used zoledronic acid since 2001 and

that use of this drug had been " increasing recently. " As of February 22,

2005, Novartis had 875 reports of jaw osteonecrosis. On the basis of these

spontaneous reports and the patient numbers involved, company researcher Dr

Diane Young (vice president of clinical development, oncology, Novartis), an

oncologist by training, came up with an incidence rate of 0.03% but

commented that " this was certainly an underestimate. " At the other extreme,

the web-based survey from Durie gives an incidence of 6.2%, which is " likely

to be an overestimate, " she said. Going back over reports from controlled

clinical trials (with follow-up from 5 to 18 months), Novartis found 2 cases

in 1334 patients on pamidronate and 4 cases out of 2730 patients on

zoledronic acid, giving an estimated incidence of around 0.15%. In addition,

Young mentioned an ongoing review of patient case histories at the MD

Cancer Center, Houston, TX; preliminary results show 18 cases from

963 patient reviews, giving an incidence of 1.9%.

Young told the meeting that there was " an important range of severity " in

this complication, and she commented that the cases she had personal

experience with required only intermittent antibiotics and the patients

continued on bisphosphonate therapy. However, oral surgeon Dr Felice O'

(Kaiser Permanente, Northern California) described several very severe

cases, including 1 woman who had a draining fistula on the outside of her

face. She described the bone necrosis as spreading " like fire " across the

jaw and said, " Nobody can tell me this is not an insignificant problem. " She

also noted that although patients stopped bisphosphonate therapy, not 1 case

has shown healing or regression, but some became worse, and in her hands the

complication has been unresponsive to antibiotics and topical therapies.

" These patients are in pain, they smell bad, they can't eat, and there's

nothing I can do to fix it. "

Proposed mechanism

In his review article, Hellstein puts forward a theory as to how the

complication may arise. Bisphosphonates work by blocking bone resorption, by

preventing osteoclasts from removing old bone, but don't affect the

osteoblasts and their ability to build new bone. Overall, the effect is a

buildup of new bone, which is beneficial in osteoporosis and other

conditions where the bones have become fragile. However, in the jaw area,

this disruption of the osteoclast-osteoblast axis may be detrimental,

particularly in individuals who have active periodontal disease and/or oral

surgical procedures that result in bone exposure and the need for remodeling

to accomplish normal healing. In these cases, impairment of the osteoclasts'

ability to remove and thus repair or contain areas of " diseased " bone may

cause the osteoblasts to " overbuild " or " wall off " the diseased bone,

resulting in a sufficient volume of necrotic bone to cause destruction.

Preexisting or superimposed bacterial cofactors produce sequestration and

possible osteomyelitis and prevent regeneration over the exposed bone.

Similarities with historical cases caused by phosphorus

The complication has been termed " bisphosphonate osteochemonecrosis of the

jaw, " but Helllstein suggests that it can also be called " bis-phossy jaw, "

and he argues that this term has a certain historical cachet, as the

complication shows similarities to " phossy jaw " seen with white phosphorus.

This complication, also known as phosphonecrosis, seen in the mid-19th

century in workers from the match-making industry; although they were often

young and otherwise healthy, they presented with an unusual necrosis of the

jaws associated with severe pain and disfigurement. (There was also the

dramatic effect of an eerie glow emanating from the mouth in a darkened

environment, the result of phosphorus deposited in the bones).

White phosphorus, the cause of phossy jaw, appears to have similar skeletal

effects as bisphosphonate therapy, Hellstein comments, and for this reason

he believes it useful to recount some of the findings recorded about that

complication. Some reports noted areas of bone exposure and sequestration,

and the sequestra were often described as porous and light in weight and

sometimes portrayed as either worm-eaten or pumicelike. However, this

description pertains only to the sequestra, Hellstein notes. In contrast,

the medullary bone was often observed to display increased trabeculations,

and chronic phosphorus exposure produced a hyperostosis of the entire

skeletal structure, with spongy bone transformed to sclerotic bone.

White phosphorus appeared to accumulate in the oral region, but whether this

was because the oral cavity was the initial portal and thus more exposed

than other regions and/or whether the faster bone turnover in the jaw

resulted in phosphorus returning to the area is unknown. Of clinical

importance are reports that it usually took white-phosphorus exposure of

months or years before the complication was seen; in addition, the risk

remained for years even after workers left their jobs, Hellstein notes. " I

cannot help but think that we may be witnessing only the tip of the iceberg

in a possible bis-phossy jaw epidemic, " he comments.

One similarity is that both phossy jaw and the bisphosphonate jaw

complications have a bacterial component in the disease process, whereas

another similar complicationosteoradionecrosis (seen in workers painting

luminous watch dials with radium) is different in that suppuration is

uncommon. In the review of 20 cases carried out by Hellstein and colleagues,

in which bisphosphonates were confirmed or suspected as cofactors, bacteria

were commonly associated with the nonvital bone fragments. The submitting

clinicians invariably reported purulence or suspected infection and gave a

clinical impression of osteomyelitis, leading Hellstein to " believe that a

bacterial component is significant in bis-phossy jaw. " However, it will take

time and multiple studies to see whether bacteria play a primary role or

merely represent secondary infections, he adds. The cases his team reviewed

and the reported observation that topical chlorhexidine has proven

therapeutically beneficial seem at least to indicate that control of surface

bacteria may help the body to recover denuded areas of bone.

Hellstein concludes that more research is needed to see what population

groups or oral factors are the best risk predictors of the complication.

" There is no doubt that bisphosphonate therapy will continue to show

substantial clinical benefits and grow in use. We need to discover the ideal

dosage, delivery route, and bisphosphonate for each patient category. "

Sources

a. Hellstein JW and Marek CL. Bisphosphonate

osteochemonecrosis (bis-phossy jaw): is this phossy jaw of the 21st century?

J Oral Maxillofac Surg 2005; 63:682-690.

b. Latest warning from FDA to dental health professionals.

The complete MedWatch 2005 Safety summary, including links to the Novartis

Dear Healthcare Professional letter and revised labels for Zometa and

Aredia. May 5, 2006. Available at:

http://www.fda.gov/medwatch/SAFETY/2005/safety05.htm#zometa2

c. Novartis Oncology. Changes made to the precautions and

post-marketing experience sections of the Aredia (pamidronate disodium)

injection and Zometa (zoledronic acid) injection prescribing information.

September 24, 2004. Available at:

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

d. 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.

e. Marx RE. Pamidronate (Aredia) and zolendronate (Zometa)

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

Maxillofac Surg 2003; 61;1115-1118.

f. Ruggiero SL, Mehrotra B, Rosenberg TJ. Osteonecrosis of

the jaws associated with use of bisphosphonates: a review of 63 cases. J

Oral Maxillofac Surg 2004; 62:527.

g. International Myeloma Foundation

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