ABSTRACT: There are several million breast cancer survivors worldwide. In the United States, 180,000 women were diagnosed with breast cancer in 1997, and approximately 97,000 of these women have an extremely low chance of a suffering a recurrence of their cancer. With an average age at diagnosis of 60 years and a 25-year expected duration of survival, the current number of breast cancer survivors in the United States may approach 2.5 million women. Since breast cancer is now being detected at an earlier stage than previously and since adjuvant chemotherapy may cause ovarian failure, an increasing number of women are becoming postmenopausal at a younger age after breast cancer treatment. This conference was convened in September 1997 to consider how menopausal breast cancer survivors should be treated at the present time and what future studies are needed to develop improved therapeutic strategies. A total of 47 breast cancer experts and 13 patient advocates participated. The proceedings of the conference are being published in six installments in successive issues of oncology. This third part focuses on the prevention of osteoporosis and the cardiovascular effects of estrogens and antiestrogens. [ONCOLOGY 13(3):397-432, 1999]
Proceedings of a Conference Held at the Boar’s 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 in vitro.
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 menopausal osteoporosis.
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 hip fractures.
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 older women.
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 alendronate doses.
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 range–finding 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 range–finding 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 menopausal women.
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 breast cancer.
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]
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