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Patients who have been receiving these bisphosphonate medications to strengthen bones should avoid having teeth pulled at all costs! They are at much higher risk for infection in the bone of the jaw. ("Osteonecrosis")
These infections are VERY hard, if not impossible, to treat and can have devastating consequences.
Attention!
Prevention is the key: PRETREATMENT phase before the
patient begins chemotheraphy with one of these drugs is probably the MOST
important stage in preventing future complications of osteonoecrosis.
The dentist can have the most significant effect of prevention by
performing any invasive dental procedure before they begin treatment
 
Osteonecrosis
Dental treatment for patients currently receiving bisphosphonate therapy
· Maintain excellent oral hygiene to reduce the risk of dental and gum infections
· Check and adjust removable dentures for potential soft-tissue injury, especially tissue overlying bone.
· Perform routine dental cleanings, being sure to avoid soft-tissue injury
· Aggressively manage dental infections nonsurgically with root canal treatment if possible or with minimal surgical intervention.
· Endodontic (root canal) therapy is preferable to extractions when possible. It may be necessary to simply remove the top of the tooth and then do root canal therapy on remaining root to avoid the
need for tooth extraction and, therefore, the potential development
of osteonecrosis.
A recent study done by UCLA/VA indicates that patients getting IV Fosamax have a higher incidence of failure to achieve integration with dental implants than patients who are not taking bisphosphonates or are taking them orally. One problem with the bisphosphonates is that they persist in bone for very long periods of time, so discontinuing use may not be effective.
It is much better to fix things very carefully BEFORE starting on the bisphosphonate drugs like Fosamax.
Preventative measures include:
* Avoiding any elective jaw procedure
* Baseline and routine dental exams including panoramic jaw radiography
* Delaying bisphosphonate therapy, if risk factors allow, to complete
dental procedures for teeth or dental structures with poor prognosis
* Educating patients about the importance of good oral hygiene, symptom
reporting, and regularly scheduled dental assessments
Patients already receiving bisphosphonates should:
* Maintain excellent oral hygiene and have routine dental examinations
* Obtain routine dental cleanings where careful attention is given to
avoiding soft tissue injury
* Have aggressive nonsurgical management of any dental infection
* Have root canal treatment if needed rather than dental extraction when
possible
Use of hyperbaric oxygen is commonly done IF necrosis begins. Has been
pretty successful for radionecrosis (following radiation treatment) but much less so for
necrosis following
the bisphosphonates.
Remember, the majority of cases with jaw infections occurred
after a dental extraction, yet some occurred spontaneously. Patients with
osteonecrosis or suspected osteonecrosis should receive immediate
attention from an oral surgeon or dental oncologist.
What is the risk for ONJ occurring in patients taking oral bisphosphonates.?
A recent article stated that the risk of jaw bone osteoporosis due to drugs
taken to prevent osteo. is very low, approx. 1:20,000.
For patients presently taking oral bis.:
Be aware that the risks of developing ONJ can be minimized but not
totally eliminated.
Good oral hygiene along with regular dental care is the best way to
lower the risk of developing ONJ.
Be aware that ONJ can occur spontaneously due to dental disease or
secondary to dental therapy. Keep attention up and let your dental and
medical professionals know if anything seems strange or different .
All routine restorative procedures can be carried out. There is no
evidence that malocclusion or masticatory forces increase the risk of ONJ.
Routine dental treatment should, generally, not be modified on the basis
of oral bisphosphonates on board the patient. However the presence of risk
factors including (1) concomitant estrogen use, (2) glucocorticoid use, (3)
over 65 year of age or (4) prolonged exposure to the oral bisphosphonates
may require consultation with an expert in metabolic bone diseases prior to
routine dental treatment.
Test for Necrosis Risk?
C-Terminal Telopeptide (CTX) - is a Marker for Serum Bone Turnover
CTX Score less than 100 pg/ml - High Risk
CTX Score 100 - 150 pg/ml - Moderate Risk
CTX greater than 150 pg/ml - Minimal or No Risk
Note: there is controversy about the meaning and applicability of these tests.
Recommendations for Dental Treatment
If you have been on the medications less than 3 years, most dental
procedures should be safe.
Discontinue bisphosphonates with approval of your physician
for 3 months prior to dental interventions that could lead to necrosis.
Restart biphosphonates 3 months after the dental procedure
There have been suggestions to use the CTX test for C-Terminal Peptides to
gauge risks of necrotic jaw damage. But many oral pathologists seem to feel that the
test does NOT provide anything more than a population overview. It probably
does NOT tell us much about an individual's risk of necrosis in a particular area of the
body.
How Does the Damage Occur?
The mouth is a breeding place for bacteria, and bacteria around the teeth can reach
the jawbone. Dr. Brian Alpert, maxillofacial surgeon at the University of Louisville
School of Dentistry, said the bisphosphonate drug may shut down the production
of cells called osteoclasts, making it difficult for the bone to respond and recover
if an infection sets in.
Alpert said that in 36 years of practice he had seen fewer than five cases of
osteonecrosis of the jaw until recently.
Now he has seen seven cases in the course of a year.
He said symptoms vary and may or may not include pain, a tooth socket that
won't heal after an extraction, or an infection around the bone with draining pus.
Some have to live with chronic pain. Some even lose their jawbone.
Newest Information from Implant Meeting.
Thanks to Dr. John Highsmith from Texas for the report.
Bisphosphonates--Arun Garg spoke about these. He's at U of Miami with Robert Marx, who pretty much discovered this problem. Here's the scoop. We all dissolve our skeletons at a rate of 0.7% per day. We also lay down new bone at the same rate. So every 143 days we have a new skeleton. Cool! Osteoporosis decreases the apposition of new bone. Calcium supplements, etc, attempt to increase new bone apposition. Bisphosphonates act by reducing the rate of bone dissolution. So if the patient now dissolves bone at a rate of 0.6% it can keep up with the lowered apposition of new bone. Unfortunately, they now know that bisphosphonates are concentrated in the head and neck bones (which form differently embryologically), so the dissolution rate is even lower. The bone gets TOO dense, choking off the blood supply, resulting in poor healing. Hence the exposed bone and happy lawyers.
So what did he recommend? If the patient has been on oral bisphosphonates for less than 3 years, take them off for 6 months before surgery, and stay off for 6 months after. If over 3 years, he recommended referring the case out. There are blood tests that can more accurately tell the level of bisphosphonates in the patent's system, which allows for a more accurate assessment.
Garg said that they had been able to make recombinant BMP-2 that is a terrific osteoinductor of bone. Put it in a rat's abdomen and it grows bone there. Put it in a collagen sponge and put it in the sinus and voila, great bone. That's the good news. The company got FDA approval for orthopedic use, which effectively eliminates the need to go to the hip in many cases. Insurance companies will pay 3800 per dose for the BMP rather than have to pay for a hip graft, and they still come out way ahead. So the manufacturer decides to pull the dental FDA application which was very close to being accepted, since dentists will not pay 3800 for a dose to do one sinus graft. And if they sell it to us for 300 then all the orthopods will buy the dental version. This is why we do not have a commercially available BMP for dentistry. Rats.
DOW JONES REPRINTS
Fosamax DrugCould BecomeNext Merck Woe
By JOHN
CARREYROU
April 12, 2006;
Merck & Co. was hit with big
punitive damages in a Vioxx case yesterday, plaintiffs' attorneys are
setting their sights on one of the company's other blockbusters:
osteoporosis drug Fosamax.
The drug maker is facing 10,000 lawsuits
related to its painkiller Vioxx, which it pulled from the market in
2004 after a study showed that using the drug for 18 months or longer
increased the risk of heart attacks and strokes. Now, adding to
Merck's woes are reports that link long-term use of Fosamax to a rare
disease in which a patient's jawbone rots and dies, called
osteonecrosis of the jaw, or ONJ.Echoing claims made in Vioxx
lawsuits, Pensacola, Fla.-based law firm Levin Papantonio Thomas
Mitchell Echsner & Proctor earlier this week filed a suit against
Merck in U.S. District Court in Fort Myers seeking class-action
status.
The suit claims that Merck sold and heavily marketed Fosamax,
the company's second-best-selling product, as safe despite knowing
about its dangerous side effect. Another law firm, Knoxville,
Tenn.-based Threadgill, filed a similar suit against Merck last
fall.With Fosamax, attorneys are closely following the Vioxx playbook
while claiming that they have more powerful cases because the link
between Fosamax and the disease is easier to establish.
"With Vioxx,
Merck can get away with saying, 'Hey, a lot of people have heart
attacks for a number of reasons that have nothing to do with our
product," says Tim O'Brien, a lawyer with Levin Papantonio. "But this
is a very unique condition that isn't caused by cigarette-smoking or
eating cheeseburgers."Merck says most of the reported cases of
osteonecrosis in patients taking bisphosphonates -- the class of drugs
Fosamax belongs to -- have been cancer patients injected with
more-powerful intravenous forms, and that a direct link to Fosamax
isn't so easily drawn.
"The cause of osteonecrosis of the jaw (ONJ) is
not well understood
and is likely to include a number of conditions,"
the company says in a statement.Oral surgeons and dentists began
noticing the link between jaw decay and bisphosphonates five years
ago. At first they thought that only the potent, intravenous versions
of the drugs, such as those administered to cancer patients to stop
cancer cells from dissolving bone, posed a risk.In the past two years,
some oral surgeons have become convinced that oral bisphosphonates
such as Fosamax can also cause jawbone death when taken for a long
period of time.
Last month, the American Association of Endodontists
issued a position statement recommending that dental surgeons should
check whether patients are on bisphosphonates and consider those
taking the drug to be at some risk for ONJ.Merck counters that "in all
of our controlled clinical trials, including the 10-year data with
Fosamax, which have included more than 17,000 patients, we have not
had reports of osteonecrosis of the jaw occurring in patients taking
Fosamax.
"The Whitehouse Station, N.J., drug maker also points out that
it inserted two paragraphs in the "precautions" section of the Fosamax
prescribing information for doctors in July 2005 after the Food and
Drug Administration requested it amend Fosamax's label.Salvatore
Ruggiero, chief of oral surgery at the Long Island Jewish Medical
Center in New York, says of the 155 ONJ cases he has come across, 22
involve patients who were taking Fosamax and other oral
bisphosphonates.
Some of these patients took Fosamax for seven or
eight years, he says. "With the oral drugs like Fosamax, exposure time
is the key," Dr. Ruggiero says.Plaintiffs' attorneys have seized on
such findings to allege that Merck engaged in the same deceptive
behavior with Fosamax as it did with Vioxx. Like Vioxx, Merck has
marketed Fosamax aggressively and today has more than $3 billion in
annual sales from the drug.
Doctors wrote 22.4 million prescriptions
for Fosamax in the U.S. last year, according to IMS Health.Henry Bone,
director of the Michigan Bone & Mineral Clinic in Detroit, says the
link between oral bisphosphonates like Fosamax and jaw decay is
overblown. Fosamax "and other bisphosphonates are very important drugs
for the treatment of osteoporosis," he says. "Rare reports of the
'osteonecrosis of the jaw' syndrome do not outweigh the benefits of
these valuable medications."
Dr. Bone has received research funding
from Merck and once worked as a paid consultant for the company.David
Tundell, a 61-year-old former aircraft maintenance officer in the Air
Force and a plaintiff in the Florida suit, says the Fosamax he took
for a year helped alleviate the osteoporosis in his hips. But he
believes it also landed him in the emergency room earlier this year
when his jaw swelled to the point where he could no longer eat. During
a three-day hospitalization, all his teeth were taken out and part of
his jaw was shaved off to remove dead bone. He says his doctor
recommended he stop taking Fosamax.
The prevalence of ONJ is hard to
determine. The
National Osteonecrosis Foundation says there are 20,000
Americans a year who are diagnosed with osteonecrosis, but it doesn't
break out the number of jaw cases. The foundation says anecdotal
evidence suggests there has been a surge in jaw cases of
late.Yesterday, a jury in Atlantic City, N.J. awarded $9 million in
punitive damages to a 77-year-old man who had a heart attack while
taking Vioxx, bringing total damages awarded to him and his wife to
$13.5 million.
It was the second Vioxx case Merck has lost."Certainly,
they're hoping for spillover" from the Vioxx cases, says John Brenner,
a partner with McCarter & English in Newark, N.J., which isn't
involved in cases with either drug. "They'll try to paint it as a
matter of pattern and practice on Merck's part. But you're going to be
hard-pressed in a trial to introduce Vioxx in a Fosamax case."Mr.
O'Brien, the lawyer with Levin Papantonio, argues that Fosamax could
become a bigger problem for Merck than Vioxx because ONJ is a
so-called "signature" disease that is rare among patients who haven't
taken bisphosphonates.
He notes that dentists now refer to the
condition as "fossy jaw" in a play on the middle syllable of the word
"bisphosphonate." Levin Papantonio, which is also involved in the
national litigation over Vioxx, is representing 200 patients in its
Fosamax lawsuit and expects that number to rise.Other pharmaceutical
companies make oral bisphosphonates for osteoporosis. French drug
maker Sanofi-Aventis SA makes Actonel and Swiss drug maker Roche AG
makes Boniva. Mr. O'Brien says his firm decided to target Fosamax
because data from the FDA's bisphosphonate safety review showed a much
higher rate of ONJ with Merck's drug than with the others.
"We'll take
on any big pharmaceutical company," he says. "We're not doing this
just because it's Merck."In the complaint it filed Monday, Levin
Papantonio alleges that the FDA's drug-safety office concluded that
Merck and other bisphosphonate makers should change their labels to
reflect the risk of ONJ as early as August 2004, 11 months before
Merck changed the Fosamax label.Merck counters that it submitted a
draft revised label for Fosamax to the agency in March 2005. An FDA
spokeswoman says it isn't "at liberty to discuss details of internal
labeling negotiations between the agency and a company." She adds that
the current Fosamax label "adequately conveys what is known about
ONJ-bisphosphonates."
Technical notes. Show to your physician.
Expert Panel Recommendation for the Prevention,Diagnosis and Treatment of Osteonecrosis of the Jaw
http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4095B2_02_12-Novartis-Zometa-App-11.htm
See also http://www.aaoms.org/docs/position_papers/osteonecrosis.pdf from the Oral and Maxillofacial surgeons.
If you are interested, please contact us at info@smilestudio.com for a .doc file version of this paper.
Check out:
http://www.tga.gov.au/adr/aadrb/aadr0608.htm
a good, current summary from the Australian government.
Some excerpts:
Currently available published incidence data for BRON are limited to retrospective studies with limited sample sizes. Based on these studies, estimates of the cumulative incidence of BRON range from 0.8%-12%.
This was derived from the number of reported (not confirmed) cases that were deemed to likely represent BRON divided by the number of alendronate pills prescribed since approval of the drug, and converted to number of patient years. While this is the best available data to date, there may be serious under-reporting and, as noted above, none confirmed. ... the estimated incidence of BRON for patients treated weekly with alendronate is 0.01-0.04%, based on prescription data in Australia. Following extractions, this rate increased to 0.09-0.34%.
Patients receiving IV bisphosphonates and undergoing dentoalveolar surgery are at least 7-times more likely to develop BRON than patients who are not having dentoalveolar surgery.
Patients with a history of inflammatory dental disease, e.g., periodontal and dental abscesses, are at a seven-fold increased risk for developing BRON.
Prior to treatment with an IV bisphosphonate, the patient should have a thorough oral examination, any unsalvageable teeth should be removed, all invasive dental procedures should be completed, and optimal periodontal health should be achieved
... the risk of developing BRON associated with oral bisphosphonates, while exceedingly small, appears to increase when the duration of therapy exceeds three years. This time frame may be shortened in the presence of certain comorbidities, such as chronic corticosteroid use.
Non-restorable teeth and those with a poor prognosis should be extracted. Other necessary elective dentoalveolar surgery should also be completed at this time. Based on experience with osteoradionecrosis, it appears advisable that bisphosphonate therapy should be delayed, if systemic conditions permit, until the extraction site has mucosalized (14-21 days) or until there is adequate osseous healing. Dental prophylaxis, caries control, and conservative restorative dentistry are critical to maintaining functionally sound teeth. This level of care must be continued indefinitely.
For individuals who have taken an oral bisphosphonate for less than three years and have no clinical risk factors, no alteration or delay in the planned surgery is necessary. This includes any and all surgeries common to oral and maxillofacial surgeons, periodontists, and other dental providers.
Patients receiving oral bisphosphonates are also at risk for developing BRON, but to a much lesser degree than those treated with intravenous bisphosphonates. BRON can develop spontaneously or after minor trauma. In general, these patients seem to have less severe manifestations of necrosis and respond more readily to stage specific treatment regimens. Elective dentoalveolar surgery does not appear to be contraindicated in this group.
However, it is suggested that if dental implants are placed, informed consent should be provided related to possible future implant failure and possible osteonecrosis of the jaws if the patient continues to take an oral bisphosphonate. Such patients should be placed on a regular recall schedule.
For those patients who have taken an oral bisphosphonate for more than three years with or without any concomitant prednisone or other steroid medication, the prescribing provider should be contacted to consider discontinuation of the oral bisphosphonate for three months prior to oral surgery, if systemic conditions permit.
Patients who are at risk can benefit by use of 0.12% chlorhexidine rinse. Only when there is frank ulceration it's time to start antibioltics.
Braces-Considerations:
Ortho is nearly impossible, apparently the whole replacement and resorbtion cycle is disrupted.
How long does ones have to be off these medications?
How long does a one have to be off these meds to rid their system of the effects of this medication....some reports are talking about ten years or more. IDF 4/06
How does this occur:
Bisphosphonates inhibit bone removal (resorption) by osteoclasts, thereby supporting the buildup of new bone. While this action may help prevent fractures in the hip, spine and other skeletal regions, it may disrupt the osteoclast/osteoblast axis in the jaws, impairing osteoclasts' ability to remove, and thus repair or contain, 'diseased' bone.
This impairment then causes osteoblasts to "overbuild" or "wall off"diseased bone. As osteoblasts build new bone, the failure of osteoclasts to remove contaminated bone interferes with the development of the necessary structure, or 'scaffolding,' on which to lay down healthy bone.
American Association of Oral and Maxillofacial
Surgeons
Bisphosphonates Can Wreak Havoc in the Mouth and Jaws, Oral and Maxillofacial Surgeon Warns
http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=109&STORY=/www/story/05-05-2005/0003545338&EDATE=
Hyperbaric O2 promotes periosteal blood supply to the bone. The bisphosphonates irreversibly alter the metabolism of the osteoclasts and so you get no or very poor bone resorbtion even if the blood supply is good.
The only good news is that there are reports coming out of Harvard suggesting that doubling or tripling the exposure to hyperbaric oxygen MAY allow resolution of these very nasty infections in the bone.
In Europe they are also employing activated oxygen (ozone) therapy to cure osteonecrosis.
News Updates
It is recommend that the least possible infection and trauma to the jaws of anyone on a cancer-related bisphosphonate for more than 6 months. Relative to implants, that would tell me that they should not be done in these patients. The Panel will also recommend not stopping the cancer-related bisphosphonates unless there is exposed alveolar bone.2/06
Bisphosphonates and osteonecrosis of the jawFDA Advisory Comments on Bisphosphonates
Understanding the pathophysiology of osteoporosis requires knowledge of the basic process of bone remodelling, a process that occurs in all bones, throughout life. At any given time, most bone units are in a resting stage, metabolically quiescent. When the remodelling process is initiated, osteoclasts are activated, and bone resorption occurs, resulting in loss of bone substance. This phase typically lasts two or three weeks. The
process is reversed with the action of osteoblasts, which lay down new bone matrix, which is in turn mineralized. The active phase of bone deposition and mineralization usually takes two or three months.
In osteoporosis, the central pathophysiological defect is increased bone
turnover, leading to skeletal fragility and increased risk of fracture
through two mechanisms. An uncoupling of the remodelling process occurs,
with bone resorption being greater than bone formation, leading to net
loss of bone, low bone mass, and thus increased risk of fracture. However,
at the same time, there is a more subtle change. Bone resorption
specifically weakens trabeculae, with trabecular strut perforation. On a
microarchitectural basis, this loss of mechanical support directly leads
to skeletal fragility and thus increased fracture risk.
Osteoporosis is defined as a progressive systemic skeletal disease
characterized by low bone mass and microarchitectural deterioration of
bone tissue, leading to increased bone fragility and risk of fracture.
Both the negative effects of increased bone turnover, and of remodelling
imbalance, is typical in osteoporosis. High bone turnover (because of
increased frequency of activation of the remodelling sequence) means that
at any given time, more bone pits can be found, decreasing biomechanical
strength. At the same time, the imbalance in remodelling means that less
bone is laid down than was removed. Both of these processes ? increased
bone turnover, and negative bone balance ? leads to rapid loss of bone in
osteoporosis.
The diagnosis of osteoporosis is clear in a patient with progressive
deformity from vertebral fractures. Some of the physical sequelae of
severe osteoporosis include: increasing number and severity of vertebral
fractures; loss of overall height; presence of a dorsal kyphosis
(dowager's hump); protruberant abdomen; crowding of the ribs and;
reduction in lung volume. These changes are commonly preventable with
appropriate treatment, which includes the class of medications known as
the bisphosphonates.
The Bisphosphonates are indicated for:
- Prevention and treatment of osteoporosis
- Treating Paget's disease of bone
- Hypercalcemia associated with malignancy
- Osteolytic lesions associated with metastatic bone disease
- Multiple myeloma
They act as bone resorption inhibitors increasing bone density by binding
to the bone matrix and slowing down osteoclastic activity, thereby
facilitating osteoblastic effectiveness.
Inorganic pyrophosphates are orally inactive, as they are hydrolyzed in
the GI tract. The bisphosphonates were developed to circumvent this
limitation, and are effective agents when administered orally (although
they are all poorly absorbed, and should be taken while fasting). They are
not metabolized significantly. Absorbed drug that is not bound to bone is
excreted unchanged by the kidneys. Bisphosphonates also have a high
affinity for calcium, and bind strongly to bone mineral, hydroxyapatite,
especially at sites of bone resorption where mineral is most exposed. The
bisphosphonate is absorbed by osteoclasts, and suppresses osteoclast
function; osteoclast apoptosis is also enhanced.
The action of bisphosphonates that should concern dentists is that they
destroy osteoclasts, without which there cannot be bone healing. In fact,
it was reported in the literature last year that:
"Osteonecrosis of the Jaw (ONJ) has been reported in patients with cancer
receiving treatment including bisphosphonates, chemotherapy, and/ or
corticosteroids. The majority of reported cases have been associated with
dental procedures such as tooth extraction. A dental examination with
appropriate preventive dentistry should be considered prior to treatment
with bisphosphonates in patients with concomitant risk factors. While on
treatment, these patients should avoid invasive dental procedures if
possible. No data is available as to whether discontinuation of
bisphosphonates therapy reduces the risk of ONJ in patients requiring
dental procedures." (http://www.us.zometa.com/hcp/safetyinformation.jsp)
Osteonecrosis of the jaw is also known as avascular necrosis of the bone
or osteochondritis dissecans (the death of bone resulting in the collapse
of the bones' structural architecture). It leads to bone pain, loss of
bone function, and bone destruction and is the result of a number of
conditions leading to an impairment of the blood supply to the bone.
As stated in the "Dear Doctor" letter from Novartis, bisphosphonates are
used to treat several other conditions related to bone metabolism and
neoplasms. What is not known yet is whether the osteoclasts ever come
back. Unlike osteoradionecrosis, this condition is not helped by
hyperbaric O2 therapy. There is also some preliminary evidence that
discontinuation of certain bisphosphonates does not seem to help.
As mentioned above, there are two forms of bisphosphonates, one with a
chloride ion for oral use that is "relatively" benign (eg. Fosamax). Oral
surgery for patients taking these is risky, at least requiring extensive
informed consent, not that there is good or sufficient information yet.
The other form with a nitrogen ion is used IV and is probably an absolute
contraindication to tooth extraction. The suggested alternative is to cut
off the tooth crown, do endo and let the tooth extract itself over time.
In 2003 and 2004, there were several reports of osteonecrosis of the jaw
(ONJ) in cancer patients receiving chronic intravenous bisphosphonates.
The reports associated pamidronate (Aredia) and zoledronic acid (Zometa)
with ONJ. Both products are produced by Novartis Pharmaceuticals
Corporation. As a result, the products' labeling was updated in the U.S.
in August 2004 and in Canada in December 2004 to include precautions about
ONJ (see quote above from website). Novartis is not the only company
marketing these drugs, there are at least five of these drugs in use. With
so many patients taking bisphosphonates for prevention and treatment of
osteoporosis he thinks we will start to see this complication with
increasing frequency.
Risk factors include systemic corticosteroid therapy and anti-cancer
treatment (both radiation and chemotherapy). The jaw bone is particularly
vulnerable to osteonecrosis because of tooth and gum susceptibility to
infection. A special added risk factors for ONJ are trauma, as from dental
procedures, and local anesthetics.
In a 2004 report from the FDA Adverse Event Reports database a total of
139 cases of osteonecrosis were identified from the marketing approval
date of Aredia, Zometa, Fosamax, and Actonel until May 24, 2004:
? 34% were associated with Aredia
? 24% per associated with Zometa
? 42% per associated with patients who received both Aredia and Zometa
? 8.6% were associated with Fosamax
? one case was associated with Actonel.
The majority of these patients were diagnosed with osteonecrosis of the
jaw. Some had a diagnosis of mixed osteonecrosis and osteomyelitis.
Because of these findings, the report stated that osteonecrosis may be a
class effect of the bisphosphonates. The oral bisphosphonates are not as
potent as the intravenous agents but they all have the same mechanism of
action. Labeling for both Fosamax and Actonel is in the process of being
updated to include this class osteonecrosis risk. Boniva labeling already
has been updated.
Conclusions to be drawn from all of this evidence to date indicates that
the majority of cases with osteonecrotic jaw lesions occurred after a
dental extraction yet some occurred spontaneously. Because of this
association with dental procedures, potential preventative measures are
suggested prior to bisphosphonate initiation.
Also, suspected
problems associated with bisphosphonates should be reported:
In the US, call the FDA MEDWATCH program at 1-800-FDA-1088 or go on-line to www.fda.gov/medwatch.
In Canada, call the Canadian Adverse Drug Reaction Monitoring Program at 1-866-234-2345 or go on-line to
http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/adverse_e.pdf.
References for the above information include:
Assouline-Dayan Y, Chang C, Greenspan A, et al. Pathogenesis and natural history of osteonecrosis. Semin Arthritis Rheum 2002;32:94.
Department of Health and Human Services, Public Health Service, Food and Drug Administration, Office of Drug Safety, Postmarketing Safety Review. August 25, 2004.
http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4095B2_03_04-FDA-TAB3.pdf. (Accessed April 14, 2005).
Anon. Expert panel recommendation for the prevention, diagnosis and treatment of osteonecrosis of the jaw. appendix 11. Oncologic Drug Advisory Committee Meeting. Novartis Pharmaceuticals Corporation. EastHanover, NJ 07936. March 4, 2005. 10/05
There is no consensus on how to manage this condition, especially when extractions are unavoidable, as in this case. What I can say is that the international literature agrees on a few things.
1. Avoid surgery (extractions) in these patients, if possible (implants included by inference).
2. If teeth have to be removed and complications develop, these are best managed conservatively - once again, avoid the temptation to open, debride & drain.
3. The risk of osteonecrosis is greater with parenteral bisphosphonates used in the treatment of myeloma, etc. but there is a risk with the oral meds.
4. Withdrawing the medication before/during/after surgery is not thought to make any difference to the outcome. 10/05
Dr Zaf Khouri Dental Surgeon & Consultant Forensic Odontologist 1100 Victoria Street PO Box 464 Hamilton NEW ZEALAND
Cancer patients receiving intravenous bisphosphonate drugs should not be treated with invasive dental procedures. Novartis Pharmaceuticals Corp. stated that osteonecrosis of the jaw (ONJ) has been observed in cancer patients who are receiving Aredia or Zometa-bisphosphonates used to treat complications of advanced cancer known as "hypercalcemia of malignancy," bone metastases from solid tumors and other conditions ADA Updates 6/05
Research:
"Bisphosphonates have a long residence time in bone. The terminal half-life of alendronate is approximately 10 years (3), and alendronate will therefore accumulate in bone for up to three half-lives, or 30 years.
Inhibition of bone resorption is sustained for at least five years after cessation of alendronate therapy (16;17), illustrating that alendronate released from the matrix during bone remodeling effectively inhibits osteoclasts. If inhibition of bone resorption is proportional to the sum of the recently administered alendronate dose plus previously administered alendronate that is released from the matrix, as proposed (3), then over time, as alendronate release from saturating bone matrix stores continues to increase, bone resorption rates could slow eventually to dangerous levels. The release of alendronate from bone matrix after 10 years of 10 mg/day is estimated to be equivalent to 2.5 mg/day orally (3).""The mineralization of bone increases during bisphosphonate therapy (19;20). The primary phase of mineralization of newly formed bone takes weeks, but the secondary phase occurs over years. As bone remodeling slows, the net age of existing bone increases, allowing more time for secondary mineralization to take place.
Increased tissue mineral content (rather than a remodeling transient or a true increase in the ratio of bone volume to total volume) is largely responsible for the sustained increases in BMD during bisphosphonate therapy (20). As tissue mineral content increases, bone
becomes tougher and is protected from fracture, but bisphosphonates at high doses produce highly mineralized and homogeneous bone that is brittle and aubject to microfracture damage (21). Preliminary reports indicate that after five years of risedronate (22) or 10 years of alendronate treatment (18), tissue mineral content, on average, is in the normal premenopausal rangeabout where one might want it. The effects of longer term accumulation are unknown, however. High-dose intravenous bisphosphonate therapy of cancer-induced bone disease has recently been associated with osteonecrosis of the jaw (23;24). Most patients were also receiving chemotherapy or corticosteroids, and without good case-control data, the role of bisphosphonates in this complication is impossible to establish. We are aware of a number of unreported cases, however, suggesting that the complication is not rare in cancer patients treated with bisphosphonates. In one study, six of 63 patients with osteonecrosis of the jaw were receiving oral bisphosphonates for treatment of osteoporosis (24). It seems likely to us that jaw osteonecrosis is a dose-related side effect of bisphosphonate therapy that is rare in the oral dose range and more common with intravenous bisphosphonate use. Good case control studies are necessary to confirm or refute this interpretation and define risk factors for osteonecrosis; duration of oral bisphosphonate therapy and cumulative
ose will be an important consideration."
The International Bone and Mineral Society. Long-Term Bisphosphonates for Osteoporosis: An Introduction Gordon J. Strewler Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA BoneKEy-Osteovision. 2005 January;2(1):6-9
http://www.bonekey-ibms.org/cgi/content/full/ibmske;2/1/
Over a three-year period, the jaws of dozens of patients who had undergone oral surgery at his hospital had failed to heal properly. Part of the jawbone had died and become exposed. "We never saw this before in the jaw" except in patients who had received radiation therapy to that part of the face.
Further investigation revealed one common thread: All of the patients had been treated with at least one of a class of drugs called bisphosphonates. Most were cancer patients who had received the intravenous bisphosphonates Zometa or Aredia or both for excessive calcium in their blood or bone tumors. But about 10% were osteoporosis patients who had taken an oral bisphosphonate, mainly Fosamax.
Ruggiero co-wrote a report on 63 patients with osteonecrosis - or bone death - of the jaw in the Journal of Oral and Maxillofacial Surgery. Six had taken Fosamax, and a seventh had taken Actonel, another oral bisphosphonate for osteoporosis. The problem doesn't appear to be as severe with oral bisphosphonates as it is with the IV drugs. Patients who have been receiving IV bisphosphonates should avoid having teeth pulled "at all costs," Based on his cases, a Food and Drug Administration (news - web sites) Web site suggests that osteonecrosis of the jaw (ONJ) is a risk of all bisphosphonates, not just the IV drugs.
Bisphosphonates remain in bone indefinitely. Ruggiero speculates that their long-term use could upset the delicate balance between cells that put calcium in bone and cells that take calcium away. The FDA (news - web sites) review concluded that all bisphosphonate labels should mention osteonecrosis. Rugierro says he has now seen a total of 12 or 13 cases of ONJ in patients treated with an oral bisphosphonate. Robert Marx, chairman of the division of oral and maxillofacial surgery at Florida's University of Miami, says he's aware of at least 40 or 50 cases of ONJ nationwide in patients who had taken Fosamax.That's a infinitely small fraction of the approximately 3 million women in the USA who are taking the drug, although most experts agree that only 1% to 10% of adverse events linked to drugs are reported While all forms of bisphosphonates, both oral and injectable, may increase the risk of bis-phossy jaw, it is the injectable medications, that appear to pose the greatest risk, according to John
W. Hellstein, DDS, MS
3/05 USA Today
Treatment:
Ozone
Biophosphonates Warning
Expert Panel Recommendation for the Prevention, Diagnosis and Treatment of Osteonecrosis of the Jaw.
Zometa (zoledronic acid), Aredia (pamidronate disodium) - Labeling revised to describe the occurence of osteonecrosis of the jaw (ONJ) observed in cancer patients receiving treatment with intravenous bisphosphonates. USA FDA (Posted 05/18/2005)
http://www.fda.gov/medwatch/SAFETY/2005/zometa_deardentite_5-5-05.pdf
Resources:
Purcell PM, Boyd IW. Bisphosphonates and osteonecrosis of the jaw.
Medical Journal of Australia 2005 Apr 18;182(8):417-8.
PMID: 15850440 [PubMed - in process]
Free Full Text http://www.mja.com.au/public/issues/182_08_180405/pur10144_fm.html
Carter G, Goss AN, Doecke C. Related Articles, Links Bisphosphonates and avascular necrosis of the jaw: a possible association.
Med J Aust. 2005 Apr 18;182(8):413-5. No abstract available.
PMID: 15850439 [PubMed - in process
http://www.mja.com.au/public/issues/182_08_180405/car10429_fm.html
Melo MD, Obeid G. Osteonecrosis of the maxilla in a patient with a history of bisphosphonate therapy.
J Can Dent Assoc. 2005 Feb;71(2):111-3 http://www.cda-adc.ca/jcda/vol-71/issue-2/111.pdf
Robinson NA, Yeo JF. Bisphosphonates--a word of caution.
Ann Acad Med Singapore. 2004 Jul;33(4 Suppl):48-9. Review.
PMID: 15389307 [PubMed - indexed for MEDLINE]
http://www.annals.edu.sg/pdf200409/V33N4p48S.pdf
Hellstein JW, Marek CL. Bisphosphonate osteochemonecrosis (bis-phossy jaw): is this phossy jaw of the 21st century?
J Oral Maxillofac Surg. 2005 May;63(5):682-9.
http://www2.joms.org/scripts/om.dll/serve?action=searchDB&searchDBfor=art&artType=abs&id=as0278239105001011&nav=abs
The American Dental Association,
http://www.ada.org/prof/resources/pubs/adanews/adanewsarticle.asp?articleid=1185
http://www.ada.org/prof/resources/topics/osteonecrosis.asp
Novartis Oncology Website (Aredia, Zometa),
http://www.us.novartisoncology.com/info/coping/dental_health.jsp?checked=y
Merck & Co. Inc, Website (Fosamax),
http://www.merck.com/newsroom/press_releases/product/fosamax_statement.html
http://www.fosamax.com/fosamax/shared/documents/english/pi.pdf
Roche Laboratories, Inc. Website (Boniva),
http://www.rocheusa.com/products/Boniva/PI.pdf
http://www.boniva.com/news/default.asp
Procter & Gamble Pharmaceuticals (Actonel)
http://www.actonel.com/global/prescribingInfo.jsp
The Journal of the American Dental Association (JADA),
http://jada.ada.org/cgi/content/abstract/136/12/1658
Journal of Oral and Maxillofacial Surgery,
http://www.joms.org/article/PIIS0278239105011870/abstract
http://www.joms.org/article/PIIS0278239104001958/abstract
American Association of Endodontists,
http://www.aae.org/rootcanalspecialists/members/updates.htm
MedicalNewsToday.com
http://www.medicalnewstoday.com/medicalnews.php?newsid=40774
The Food and Drug Administration,
http://www.fda.gov/medwatch/SAFETY/2004/ZometaHCP.pdf
http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4095B2_03_02-FDA-TAB1.doc
http://google2.fda.gov/search?client=FDA&site=FDA&oe=&lr=
&proxystylesheet=FDA&output=xml_no_dtd&getfields=*&q=Osteonecrosis+of+the+Jaw+&as=GO
National Institute of Health Publication Library (several abstracts and publications),
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=PubMed&term=Osteonecrosis+of+the+Jaw&tool=QuerySuggestion
The Medical Journal of Australia,
http://www.mja.com.au/public/issues/182_08_180405/pur10144_fm.html
Many thanks to Dr. Dan Petersen of Gering, Nebraska for his major assistance in preparation of this information. |
