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Osteonecrosis of the Jaw, Androgen
Deprivation, and Bisphosphonates
(May 2007)
An article in the May
issue of the Journal of Clinical Oncology, "Randomized Controlled
Trial of Annual Zoledronic Acid to Prevent Gonadotropin-Releasing
Hormone Agonist-Induced Bone Loss in Men with Prostate Cancer"
demonstrated in osteoporotic men (T score > -2.5) on ADT with
non-metastatic disease that a single dose of 4 mg of the bisphosphonate,
Zometa, increased bone mineral density after one year by 4.0% vs.
a 3.1% loss in the placebo arm. This finding will likely further
increase the use of this class of drug in prostate cancer.
Current clinical
practice guidelines now endorse the use of a much higher dosage regimen,
i.e. 4 mg IV every three weeks in men with objective bone metastases, a
therapy used with regularity. The finding in the JCO study that by
comparison such a minimal exposure as 4 mg yearly of this
bisphosphonate yields real benefit in the avoidance of androgen
deprivation (AD) related bone loss is very good news. An excess of 200
case reports have suggested that heavier dosing and/or long-term usage
of bisphosphonates is associated with a rare, but significant toxicity:
osteonecrosis of the jaw (ONJ). The principal affected site is the
mandible. No clinical trials have as yet established the true incidence
of this complication, but based on these case reports, an initial
estimate is between 1% and 10%.
A comprehensive review
of this issue, "Osteonecrosis of the Jaw in Cancer Patients Receiving IV
Bisphosphonates", was presented by Poznak and Estilo, in Oncology,
August 2006. The mechanism leading to the bone destruction underlying
this pathology is not understood, but suppositions invoke the
possibility that the inhibition of osteoclast function by these drugs
"may predispose bone to delayed bone remodeling", as might occur after
dental extractions. The condition usually involves exposed bone in the
maxilla or mandible. Other explanations include disruption of bone
microarchitecture, or inflammation/infection as contributing factors. In
this regard it may be relevant that AD triples the risk of periodontal
disease (Urology 2007;177).
"Although it is often
associated with a recent dental surgical procedure, spontaneous ONJ can
also occur. Patients commonly present with symptoms such as "pain,
drainage, swelling, and anesthesia/paresthesia." The exposed bone
appears "necrotic and non-vital." Evidence of bony destruction can be
seen on CT/MRI images and increased tracer uptake is seen at those sites
on bone scans. "Histologically necrotic bone with associated
Actinomycetes colonization is often seen. Soft tissue or gingival
biopsies reveal inflammed squamous mucosa or granulation tissue."
The incidence increases
with the duration of treatment. The review noted that "the median time
to ONJ in patients [receiving bisphosphonates] with metastatic breast
cancer or multiple myeloma to be 39 to 72 months in those treated with
pamidronate [Aredia] and 18 months in those treated with zoledronic acid
[Zometa]." Other studies found a lesser incidence of ONJ with
pamidronate therapy. A better estimate of incidence will likely emerge
from the inclusion of monitoring for ONJ in two upcoming trials using
long-term bisphosphonates in breast cancer.
A report (Leukemia.
2007, Apr 5),"A different schedule of zoledronic acid can reduce the
risk of osteonecrosis of the jaw in patients with multiple myeloma"
compared the occurrence of ONJ in one group of patients receiving
monthly bisphosphonate therapy until intolerance, to a group that
received monthly treatment for one year and then every three months
thereafter. The incidence of adverse skeletal events was similar, but
the reduced schedule group had an eight-fold reduction in ONJ. ONJ was
higher in those receiving Zometa vs pamidronate ( 9.1 vs 1.6 per 100
person years).
ONJ is not confined to
those persons receiving the more potent bisphosphonates, pamidronate or
zoledronic acid. Alendronate (Fosamax) and risedronate (Actinel) are
commonly used as long-term therapy for cancer-unrelated osteoprosis. A
March 20, 2007 report in the Annals of Internal Medicine
evaluated the use of Fosamax in prostate cancer: "Effect of once-weekly
[70 mg] oral alendronate on bone loss in men receiving androgen
deprivation [ADT] therapy for prostate cancer: a randomized trial." This
study of 112 men with non-metastatic cancer receiving ADT therapy found
that "In men treated with alendronate, bone mineral density increased at
1 year by 3.7% at the spine and 1.6% at the femoral neck." The
respective figures for the placebo group were losses of 1.4% and
0.7%. The observation that "At baseline, 39% of men had osteoporosis and
52% had low bone mass" just underscores the recommendation that all
men undergo a DEXA study before starting ADT.
The dental community is
very sensitized to the risk of ONJ posed by bisphosphonate useage since
they are the professionals who perform the dental surgery and are called
upon to treat the condition. The Oncology review points out the
obvious, that "Oral health is an important component of the patient's
overall care" and recommends a dental assessment prior to the start of
antiresorptive drugs. There is no standard treatment for ONJ. "General
approaches to managing ONJ include the use of antibacterial rinses,
conservative and minimal debridement with focus on removing sharp edges
of bone, and antibiotic therapy if superinfection is present."
Bottom Line:
For the oncology community, the important message is to be aware of the
risk of the infrequent occurrence of osteonecrosis of the jaw associated
with bisphosphonate useage during ADT therapy. This knowledge should
lead to the regular inspection of the oral cavity and an inquiry about
symptoms in every person on long-term bisphosphonate treatment.
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