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January 1999
Dr. Paul Walker
Palliative Care Unit, Edmonton
Bisphosphonates are analogues of inorganic
pyrophosphate. Their use is well established for treatment of
osteoporosis and Paget's disease. In the oncology setting, clodronate
and pamidronate are the drugs of this class that are most frequently
used and studied. The mechanism of action of bisphosphonates
is inhibition of osteoclast mediated bone resorption caused
by cancer. These drugs have been administered both orally and
parenterally, however, the oral bioavailability is extremely
poor in the order of less than 5%. Over the last 10 years, this
field of research has been growing rapidly and more recently
well performed randomized controlled trials (RCTs) have been
performed. At present RCTs support the use of bisphosphonates
to treat hypercalcemia of malignancy and these drugs are now
the agents of choice for this condition. Several RCTs have explored
the use of bisphosphonates as an adjunct to assist in controlling
bone pain [1-4]. These studies have shown significant benefit
in reducing bone pain with minimal side effects in patients
with different cancers. Prevention of complications due to osteolysis
such as pathological fracture, need for palliative radiotherapy,
surgery to treat pathological fractures, and spinal cord compression,
have been investigated in breast cancer [5-10] and in multiple
myeloma [11-14]. In these studies, complications due to osteolysis
were significantly reduced as was bone pain. Three studies [15-17]
have confirmed benefit of bisphosphonates for treatment of steroid
induced osteoporosis. A recent systamatic review [18] and various
expert opinions support the use of bisphosphonates as standard
therapy in cancer [19,20].
In spite of this level I evidence
from multiple RCTs, in our group's clinical practice it is
rare that we see bisphosphonates used other than in the setting
of hypercalcemia of malignancy. This leads us to speculate
that these drugs may be under-utilized for treatment of bone
pain, prevention of complications due to osteolysis, and prevention
of steroid-induced osteoporosis. It is apparent that the use
of bisphosphonates has increased with the publication of the
previously mentioned trials, however it is troubling that
many patients are still denied the proven palliative benefits.
As with any new finding it takes time
for changes in practice to occur (until recently [14,21] a
survival benefit had not been shown, which has now prompted
more excitement among the oncology community). However, with
the large amount of evidence accumulated it is time to go
forward with guidelines for the use of these agents in order
to promote palliation. To this end it would be desirable that
the groups responsible for cancer care convene to determine
consensus guidelines. Standard chemotherapy agents have been
utilized with less evidence than we now have for a beneficial
effect of bisphosphonates.
Costs remain a considerable concern
as these agents are expensive. It is significant praise for
the effectiveness of these drugs that others have suggested
that cost reductions could occur through decreases in hospitalization
and need for radiotherapy and surgery. However, a cost saving
benefit should not be required for implementation as there
are few interventions in medicine that actually save money.
Oral administation of these agents
has been effective in many studies [4,7,10-12,15-17]. However,
due to the extremely poor oral bioavailability of these agents,
parenteral administration is often utilized, especially in
treating hypercalcemia of malignancy and acute bone pain.
The inconvenience of IV administration represents a further
obstacle to providing these benefits to our patients. For
some groups monthly intravenous infusions of pamidronate have
become the standard, however our group has explored the use
of subcutaneous administration of clodronate [22,23], which
can be conveniently administered in the home via hypodermoclysis
and may offer cost savings.
In summary, an evidence based medicine
approach supports the use of bisphosphonates based on level
I evidence. The responsibility remains with treating physicians
to change our practices and overcome the financial and logistic
obstacles to bring these benefits to the cancer sufferer.
References:
- Ernst DS, MacDonald RN, Paterson
AHG, Jensen J, Brasher P, Bruera E. A Double-blind crossover
trial of intravenous clodronate in metastatic bone pain.
J of Pain & Symptom Manage 1992; 7(1):4-11.
- Ernst DS, Brasher P, Hagen N,
Paterson AHG, MacDonald RN, Bruera E. A randomized, controlled
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ME, Eastell R, Coleman RE. Relationships between biochemical
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of pamidronate for metastatic bone disease. Annals of Oncol
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SH. Effect of oral clodronate on metastatic bone pain: A
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(APD). The Lancet 1988; 143-46.
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Bruera E. Subcutaneous clodronate. The Lancet 1996; 348:345-6.
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