Treatment of Estrogen Deficiency Symptoms in Women Surviving Breast Cancer, Part 3
Treatment of Estrogen Deficiency Symptoms in Women Surviving Breast Cancer, Part 3
Proceedings of a Conference Held
at the Boars Head Inn, Charlottesville,Virginia
September 21-23, 1997
Nelson B. Watts, MD: All of the bisphosphonates share a common
chemical structure in which two phosphonic acids are bound to a
carbon. These compounds avidly bind to surfaces of metabolically
active bone. They are effective when given intravenously or orally
but are poorly absorbed when given by mouth. For this reason, they
must be taken on an empty stomach, with water only, and at least 30
minutes must be allowed for adequate absorption before any food is ingested.
Bisphosphonates are not metabolized, and excretion by the kidneys is
the only means of eliminating these agents from the body. For these
reasons, patients who have renal insufficiency should be given these
agents with caution, if at all.
Once absorbed, bisphosphonates bind to bone surfaces; later, after
bone remodeling is complete, they are buried away from active bone
surfaces and are no longer pharmacologically active. This results in
very long retention of these drugs in the body, in some instances,
for 10 years or more.
The specific action of bisphosphonates is inhibition of osteoclasts
that resorb bone. Bisphosphonates may also interfere with recruitment
of precursor cells, the differentiation of precursor cells into
mature osteoclasts, and increase osteoclast apoptosis.
Bisphosphonates can be altered chemically by modifying one or both of
the two side chains, which changes not only their potency but also
their side effect profiles. These targeted alterations in structure
increase the antiresorptive effects on bone from 100- to 1,000-fold
Sequential changes in these side chains have resulted in the
development of first-, second-, and third-generation compounds.
Etidronate (Didronel), a first-generation bisphosphonate, has been
used for the treatment of bone diseases for over 2 decades. Second-
and third-generation bisphosphonate agents, such as risedronate and
ibandronate, are already in the advanced phases of clinical trials.
Most of the data on osteoporosis prevention and treatment has been
obtained with alendronate (Fosamax), the first bisphosphonate
approved by the FDA for both the treatment and prevention of
Phase III Trial of Alendronate
The average 30-year-old woman loses bone gradually, and by age 70 has
lost 20% of her spinal bone mass, and, therefore, falls two standard
deviations below the mean bone density for a 30-year-old. The average
age of women enrolled in the phase III trial of alendronate was 67
years and the average bone density was about 2.3 standard deviations
below peak bone mass for a 30-year-old. Approximately 1,000 women
participated in the trial at 18 centers in the United States and 19
centers throughout the world. Patients were randomized to receive a
placebo or one of three doses of alendronate (5, 10, or 20 mg/d).
Changes in spinal bone mineral density constituted the objective end
point of the study.
All patients received calcium, which prevented bone loss in the
control group. A dose-response effect of alendronate was evident,
with the maximal effect observed with the 10-mg dose, which, in the
US cohort, resulted in a 6% increase in spinal bone mass at 1 year,
8% at 2 years, and 10% at 3 years (Figure
1). The 20-mg dose afforded no additional benefit. Based on
these data, the recommended alendronate dose to treat osteoporosis
was set at 10 mg/d.
Fracture Intervention Trial
Another study, the Fracture Intervention Trial, examined the rate of
fractures in over 2,000 women. Entry into the study required a
previous vertebral fracture and low femoral neck bone mineral
density. When compared with placebo, alendronate treatment for 3
years resulted in a 55% reduction in clinically apparent vertebral
fractures, a 48% reduction in wrist fractures, and a 51% reduction in
The data from these two studies are intriguing, because the
antifracture effect was site-independent, whereas the improvement in
bone mass was not. Spinal bone mass increased to a greater extent
than hip mass, which, in turn, was greater than wrist bone mass.
When comparing studies, it is notable that fracture data are derived
from studies of older women. Younger women have a lower fracture rate
and do not generate a sufficient number of fractures for valid
statistical analysis. For that reason, fracture rate studies involve
Other Trials of Alendronate
The Early Postmenopausal Intervention Cohort, or EPIC, included a
placebo arm, 2.5- and 5.0-mg alendronate arms, and an open-label
estrogen-progesterone arm (Figure 2
and Figure 3). Because the use of
estrogen in this trial would prevent blinding, women were initially
asked if they would be willing to take estrogen, and were then
assigned to one of two strata: Women willing to take estrogen were
assigned to stratum 1 and were randomized to placebo, one of two
doses of alendronate (2.5 or 5.0 mg/d), or an estrogen-progestin
combination. Those not willing to take estrogen were assigned to
stratum 2 and were randomized only to placebo or one of the two
Data from stratum 2 subjects revealed a 1% per year bone loss in the
spine, total hip, and total body among the placebo recipients despite
calcium supplementation. Both the 2.5- and 5.0-mg alendronate groups
showed an increase in bone mass, with the 5.0-mg group showing the
greatest effect. In the 5.0-mg alendronate group, 86% of patients
gained bone but 14% did not. The latter finding has convinced me to
monitor bone markers or repeat bone density measurements in order to
identify nonresponding patients.
Longer-term follow-up data are available from a dose
rangefinding study. In the placebo group, after 3 years
there was a 4.5% loss of bone mass in the lumbar spine and a slightly
lesser loss of total body bone mass. In women who received of 5 mg of
alendronate daily for a total 5 years, there was an early increase in
spinal bone mass of 2% to 3% and then stabilization after
approximately 1 to 2 years until year 5.
Alendronate vs Estrogen
Data from stratum 1 patients in the EPIC study provide a comparison
between alendronate and estrogen. Patients receiving calcium plus
placebo lost bone, while patients receiving calcium plus alendronate,
either 2.5 or 5.0 mg/d, increased bone mass but not to the same
extent as the estrogen-progestin group (Figure
2 and Figure 3). Similar
findings were noted with respect to total body and forearm bone
density measurements. Alendronate and estrogen-progestin produced
similar improvements in total body bone density, but
estrogen-progestin was slightly superior in increasing forearm bone
density. Because these patients do not yet have established
osteoporosis, prevention of bone loss is the overriding
consideration; therefore the better effect of
estrogen-progestin may not be clinically important.
With respect to the dose rangefinding study, data extend to 5
years in the alendronate groups and to 3 years in the placebo group.
After 2 years, the 20-mg arm was terminated, which permitted
evaluation of what happens after the agent is stopped. The
deoxypyrid-inoline collagen cross-link marker fell by 40% upon
initiation of alendronate and remained suppressed as long as
treatment was continued but quickly returned to baseline levels upon
cessation of therapy. This suggests that bone remodeling is
controlled for as long as treatment is given but reverts to baseline
soon after it is stopped.
Bone mass increased with the 20-mg dose over the 2 years of
treatment. Then, when the drug was stopped, bone mass remained higher
than in patients who continued taking the 5-mg daily dose over the
next 3 years. It is of interest that the decline in bone mass
observed after stopping alendronate was lower than that seen in the
placebo group. This suggests some long-term residual effect of drug
remaining in bone. The residual effect was observed at all bone sites.
These studies also provide information about drug tolerability. In
the prevention trials, there were no differences in side effects
between patients taking placebo and alendronate. This is interesting,
since some patients who took alendronate after the drug was approved
experienced gastrointestinal side effects, particularly esophagitis.
Other bisphosphonates are also currently under study. At the American
Society for Bone and Mineral Research (ASBMR) meeting in September
1997, data on the third-generation bisphosphonate risedronate were
presented. The results show similar increases in bone mass
compared with alendronate.
Published data are also available from two recent studies from
England and France, showing the effectiveness of intermittent
cyclical etidronate for the prevention of bone loss in recently
Bisphosphonates are about as effective as estrogen for both the
prevention of bone loss in the early postmenopausal period and for
the treatment of established postmenopausal osteoporosis. At least in
younger women, it appears that therapy must be continued indefinitely
for ongoing efficacy.
The bisphosphonate regimen is somewhat restrictive, in that patients
must take the medication first thing in the morning after an
overnight fast and ingest nothing but water for 30 minutes while
remaining upright. A small percentage of patients have problems
complying with this regimen. Otherwise, these agents are well
tolerated and very safe. These results make bisphosphonates an
excellent choice for most women who are at risk for osteoporosis and
cannot or will not take estrogen.
Additional information on metastatic disease makes the
bisphosphonates particularly attractive for breast cancer survivors.
Several of these agents have been shown to reduce the risk of
fractures from skeletal metastases and slow the progression of
metastases. By slowing remodeling, bone becomes a less hospitable
environment for foreign invaders. For all of these reasons,
bisphosphonates provide an attractive option for women surviving
Dr. Melody Cobleigh asked about methods for reducing the cost of
these agents. In response, Dr. Watts commented on the use of
ibandronate every 3 months by intravenous injection. This method
could be more cost-effective while still practical.
Dr. JoAnn Pinkerton asked for clarification about the incidence of
gastric and esophageal ulcers and pancreatitis and the potential for
delayed side effects with a drug that remains in the bone over the
long term. Dr. Watts replied that the rapid return of bone remodeling
upon cessation of the drug is reassuring. The release of drug from
cryptic sites in bone over time might provide continued supply of
pharmacologically active drug, but this is calculated to provide the
equivalent of only 2 weeks of drug in a patient stopping medication
after 10 years. Dr. Watts commented that in his clinical practice,
10% to 15% of patients experience gastrointestinal side effects from
alendronate due to local irritation of the esophagus. He believes
that most patients who have symptoms stop the drug and, thus, do not
develop esophageal ulcers. He was unaware of pancreatitis or gastric
ulceration in association with ingestion of bisphosphonates.
Another question focused on the potential for differential effects of
bisphosphonates on bony metastases. Dr. Watts concurred that this
might be a possibility, but that no data yet support this concept.
Dr. Rena Vassilopoulou-Sellin asked whether or not data exist to
determine the long-term effects of a drug that can reside in bone for
as long as 20 to 40 years. Dr. Watts cited 8-year follow-up data in
patients treated with etidronate that demonstrated no detrimental
effect. The main concern would be complete inhibition of
remodeling, which does not appear to happen.
Dr. Watts was asked about his approach to the patient who finds
alendronate intolerable due to gastrointes-tinal side effects. He
advised switching such patients to cyclic etidronate, even though
this drug does not have FDA approval for osteoporosis prevention. He
advised the use of intravenous pamidronate (Aredia) every 3 months
for those who cannot tolerate oral bisphosphonate. He indicated,
however, that there are no direct comparative data on the relative
efficacy of these alternative approaches.
Dr. Watts was then asked about the combined use of bisphosphonates
and calcitonin or estrogen for severe osteoporosis. He was aware of
no data on the combination of bisphosphonates and calcitonin. He
commented on two small open-label studies in both older and younger
women demonstrating similar effects from estrogens and
bisphosphonates separately and slightly greater effects when a
bisphosphonate and estrogen were used in combination.[11,12]