The bisphosphonates have now joined an elite
group of drugs that have annual sales greater than $1 billion.
Although the major therapeutic target of these agents is
osteoporosis, their use in cancer, particularly in osteolytic bone
disease due to breast cancer and myeloma, is growing very rapidly.
Pamidronate (Aredia), the only bisphosphonate currently approved for
this indication in the United States, is now prescribed for the
majority of patients with myeloma, as well as a substantial number of
patients with breast cancer.
Berenson and Lipton have been at the forefront of studies of
pamidronate in osteolytic bone disease due to myeloma and breast
cancer. The current widespread use of this drug in patients with
osteolytic bone disease is due, in large part, to their efforts and
those of their collaborators. Therefore, it is very useful to read
about their current thoughts on the application of these agents in
patients with osteolytic bone disease. Their perspective is
particularly instructive because of the many outstanding questions
regarding the use of bisphosphonates in cancer patients. These include:
Which bisphosphonate should be used for osteolytic bone disease?
How should these agents be administered, and for how long?
What is the mechanism of action of bisphophonates in this setting?
Are any better bisphosphonate agents on the horizon?
Berenson and Lipton address a number of these questions in their
article. However, at present most of the answers are based on
educated guesses rather than experimental data. This is due, in large
part, to difficulties in interpreting studies conducted in patients
with advanced disease because of the presence of so many confounding
variables. These questions, however, require definitive answers as
soon as possible.
Effects of Bisphosphonates on Survival
The issue of the effects of these agents on survival is very
important. One would expect that the reduction in skeletal-related
events noted in both patients with myeloma and breast cancer would
lead directly to increased survival. However, there is another issue,
namely, that bisphosphonates may actually reduce tumor burden. This
cannot be doubted from the animal studies,[1-2] and is also apparent
from recent clinical studies reported by Diel et al and Powles et
al. In these studies, bisphosphonates not only reduce osteolytic
bone lesions and skeletal-related events but also decrease tumor
burden in bone.
These findings raise the question of how the reduction in tumor
burden is occurring, and whether it has any significance for the
patient. I believe it may. By the time that the patient develops
advanced bone metastases, the actual burden of tumor cells in bone
may be relatively large since bone is such a great potential
reservoir for tumor cells. Any successful reduction in total tumor
burden is likely to improve patient outcome.
How Do Bisphosphonates Reduce Tumor Burden?
An obvious question that arises from these studies is, by what
mechanism do bisphosphonates reduce tumor burden? One possibility is
that these agents may increase target cell apoptosis, as has been
previously shown in osteoclasts in vivo and myeloma cells in
vitro. Another, and in my opinion more likely, explanation is that
bisphosphonates may reduce tumor burden by changing the bone
microenvironment; specifically, they may decrease the production of
active forms of bone-derived tumor growth factors, which can enhance
the aggressive behavior of the tumor cells in these sites.
With regard to the use of bisphosphonates in bone disease due to
myeloma, Dr. Berensons experience has been limited to
pamidronate, and he is a great advocate for its use. The data
reported by Berenson are very impressive. Pamidronate is clearly
effective in reducing skeletal-related events by about 50%.
Berenson and Lipton are quite critical of studies of other
bisphosphonates, and emphasize that agents such as clodronate are
less potent than pamidronate. My view is that, when used in
appropriate doses, clodronate or any of the other newer
bisphosphonates (with the exception of etidronate [Didronel]) will
likely be as effective as pamidronate in this situation. It is
difficult to compare directly the efficacy of these drugs without
side-by-side comparisons of their use at maximal doses.
A Striking Finding
A recently published paper by Diel et al suggests that clodronate
reduces tumor burden not only in bone but also at other sites. Drs.
Berenson and Lipton mention but do not discuss this article. Since
Dr. Lipton has been at the forefront of studies in breast and
osteolytic bone disease, it would have been useful to have heard his
comments about this article.
This is a very striking finding that is very controversial and will
obviously need confirmation by other groups and with other
bisphosphonates. Its recent publication in The New England Journal
of Medicine was also widely publicized in the lay press (eg, Wall
Street Journal, August 6, 1998, and USA Today, August 6, 1998).
These striking results in myeloma and breast cancer raise the
possibility that other cancers may also be responsive to the
bisphosphonates. This looks like a foregone conclusion with respect
to tumors that destroy bone by mechanisms similar to those operating
in breast cancer and myeloma (namely, osteoclastic resorption).
However, in tumors, such as prostate cancer, that cause osteoblastic
metastases, the appropriate role for bisphosphonates remains unclear.
There is a paradox inherent in this situation. These tumors are
frequently associated with a marked increase in markers of bone
resorption,[8,9] and yet the pathologic and radiologic lesions are
predominantly osteoblastic. Some clinical data suggest that
bisphosphonates may be useful in prostate cancer. However, these
data are not as convincing as those in osteolytic bone disease.
What Does the Future Hold?
Finally, what does the future hold for these agents? Clearly, even
more potent bisphosphonates are on the horizon that will likely be
introduced in the next few years. However, it is not clear whether
these new agents will have increased efficacy or produce greater
effects than those currently observed with pamidronate.
Nevertheless, the greater potency of new bisphophonates may be
helpful in other respects. One problem with pamidronate is that it is
approved for administration only via a monthly intravenous infusion.
A drug that can be given by a simple intravenous push or taken orally
without causing the problems associated with oral pamidronate would
be much more convenient, and presumably less expensive. This may be
the major advantage of the new-generation, more potent
bisphosphonates for osteolytic bone disease.
1. Sasaki A, Boyce BF, Story B, et al: Bisphosphonate risedronate
reduces metastatic human breast cancer burden in bone in nude mice.
Cancer Res 55:3551-3557, 1995.
2. Yoneda T, Sasaki A, Dunstan C, et al: Inhibition of osteolytic
bone metastasis of breast cancer by combined treatment with
bisphosphonate and tissue inhibitor of matrix metalloproteinase-2. J
Clin Invest 99:2509-2517, 1997.
3. Diel IJ, Solgmayer EF, Goerner R, et al: Reduction of new
metastases in breast cancer by clodronate. N Engl J Med 339:657-663, 1998.
4. Powles TJ, Patterson AHO, Nevantaus A, et al: Adjuvant clodronate
reduces the incidence of bone metastases in patients with primary
operable breast cancer (abstract). Proc Am Soc Clin Oncol 17:468a, 1998.
5. Hughes DE, Wright KR, Uy HL, et al: Bisphosphonates promote
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