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Recommendations by Our
Area Dental Professionals:
Most of the adverse events have occurred in patients taking
intravenous bisphosphonates such as Pamidronate (Aredia) and
Zolendronate (Zometa). However the oral bisphosphonate
Alendronate (Fosamax) has also been implicated in a few cases.
Patients taking the intravenous forms are usually being treated for
cancer, while most patients on Fosamax are taking it for
osteoporosis. The osteonecrosis usually presents as an area of
exposed, necrotic bone that may or may not be painful.
The reason for this effect being limited to the jaws is probably due
to the fact that the higher turnover rate of bone in the jaws can
concentrate the bisphosphonate.
The mechanism of action underlying this side effect is not
completely clear but two theories seem to present the strongest
cases. First, bisphosphonates have been found to be
antiangiogenic. The second proposed mechanism is based on
osteoclast inhibition, which is the primary mechanism of action for
these drugs. If necrotic bone cannot be resorbed by the
osteoclasts in the course of normal healing, then the necrotic bone
will inhibit healing and affect blood supply to the area.
Precipitating factors associated with the osteonecrosis include
dental extraction, severe periodontitis, spontaneous exposure,
periodontal surgery, dental implants and root canal surgery, in that
order of prevalence.
Current recommendations include completion of needed or
anticipated dental work prior to beginning bisphosphonate therapy,
especially for the IV cases. This is similar to the protocol
recommended for patients requiring radiotherapy for head and neck.
The difference is that radionecrosis responds to hyperbaric therapy,
bisphosphonate related osteonecrosis does not. This is the
most importnat concept for intravenous cases. Other suggestions
include performing coronectomies rather than extractions in these
patients and dental implants are not recommended. It has
been recommended by Dr. Geoff Engelhardt's article that a rinse
of Chlorhexidine follow extractions.
Some research has found that patients taking
Fosamax for less
than three years require no alteration in treatment. In those
on the drug for over three years it is recommended that patients
discontinue oral Alendronate for three months, complete their dental
care, then start the Fosamax three months after care is completed.
This may rise some questions as the effective time of osteoclast
inhibition is around ten years.
If you develop osteonecrosis of the jaws, please see an oral
surgeon immediately. Treatment may involve sequestrectomy of
the necrotic bone, but success rates for this treatment vary.
Another treatment option may be a regimen of antibiotics followed by
regular rinse with 0.12% Chlorhexidine.
A 91% success rate has been recorded with this regimen in
eliminating pain though exposed bone remains.
The risk in Fosamax users is extremely low but exists, so the
protocol recommended should be followed to protect your patients.
Periodontal Associates, Dr. Lindeberg and Dr. Johnson 5/06
newsletter.
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Dental treatment for patients currently
receiving bisphosphonate therapy
· Maintain excellent oral
hygiene to reduce the risk of dental and periodontal 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 carry out coronal amputation with subsequent root canal therapy on
retained roots to avoid the
need for tooth extraction and, therefore, the potential development
of osteonecrosis.
Osteonecrosis of the jaws is seen mainly with drugs such as
Zometa or Aredia which are bisphosphonates given to reduce
hypercalcemia seen in certain cancers. 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.
Appendix 11: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
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Braces-Considerations:
Ortho
is near 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
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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.
T 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.
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News Updates
Please talk to your doctor about bisphonates. Some
bisphonates, like tamoxifen, are given by injection to help guard
against breast cancer recurrence. Others like Fosamax are given
orally to help prevent and treat osteoporosis. It has been observed
within the last few year that there is a relatively uncommon but
potentially serious effect of bisphonates, especially with the
injectable forms. A complication known as osteonecrosis, literally,
dissolving of bone, can occur after surgical procedures such as
tooth extractions. This appears to occur with unusual frequency
in people taking bisphonates. This post-treatment condition is
uncommon, but the research on it is in its infancy, so we can’t
really say exactly what the risk is statistically. Talk to your
physician if you’re taking or thinking of taking a bisphonate,
especially Fosamax. These drugs are absorbed by bone and stay in
the bone a long time, perhaps years after you stop taking the drug.
Ask questions and make an informed decision on whether it’s right
for you to take a bisphonate. If you’re considering any surgery,
dental or medical, it’s important that you inform the surgeon if
you’re taking this medication.7/06
Bisphosphonates, including alendronate (Fosamax®),
and ONJ
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 jaw
FDA 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 cutoff 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.
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 but much less so for necrosis
following
the bisphosphonates.
Remember, the majority of cases with osteonecrotic jaw lesions
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. Also, suspected
problems associated with bisphosphonates should be reported:
"Osseointegrated dental implants are
contraindicated and may result in
further osteonecrosis".
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
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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
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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/
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Jaw Surgery Failure
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
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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
Free Full Text
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
Free Full Text
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]
Free Full Text
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
ADA Informed Consent
Penn
AGD Informed Consent
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March 21, 2008
