The occurrence of bone metastasis is a common event in the natural history of breast cancer. In fact, bone localization is the most frequent site of metastatic disease in patients with advanced breast cancer.
Cytotoxic chemotherapy or hormonal agents used systemically are the preferred forms of treatment, but they usually are associated with only temporary control of symptomatic disease. The ultimate prognosis in patients with metastatic breast cancer of the bone is generally poor, but a proportion of these patients may survive longer and thus require palliative treatment of the symptoms and complications related to their bone metastases.
Alternative palliative bone-directed therapies involve localized radiation therapy and radioactive bone-seeking agents (strontium-89 and samarium-153), which usually are used to prevent pathologic fractions and reduce pain.[22-24]
Because of their activity as inhibitors of osteoclastic bone resorption, bisphosphonates have been shown to be effective in the palliative treatment of women with osteolytic bone metastases. The two most popular agents, clodronate and pamidronate, have been extensively investigated in multicenter clinical trials performed in the last 10 years (Table 2). These agents have demonstrated efficacy in the management of malignancy-associated hypercalcemia, replacing other agents such as calcitonin, corticosteroids, and plicamycin. Their use in patients with metastatic breast cancer has been associated with a delay in the onset of skeletal-related events and with improvement in pain control and overall quality of life.[25,26]
A series of phase II studies demonstrated the activity of bisphosphonates used as single agents in controlling symptomatic osteolytic bone metastases and reducing bone pain. The symptomatic efficacy appeared to be dose dependent, particularly for the oral agents, because of their poor absorption. These interesting results prompted randomized clinical trials to evaluate the efficacy of the drugs in the management of osteolytic bone disease.
In the first study, Paterson et al used a double-blind, randomized, placebo-controlled trial to investigate oral clodronate at a dose of 1,600 mg/day. A total of 173 patients with osteolytic metastatic breast cancer were enrolled, and 85 received clodronate. In those receiving clodronate, the rate of all morbid skeletal events -- including vertebral fractures and deformities -- was significantly reduced (P<0.001). No significant differences in survival or side effects were observed between these two groups.
In 1993, van Holten-Verzantvoort et al published the results of a randomized study using oral pamidronate in osteolytic metastatic breast cancer. Eighty-one patients were treated with oral pamidronate; due to severe gastrointestinal toxicity, a starting dose of 600 mg/day used in 29 patients was reduced to 300 mg/day in 52 patients. When compared with 80 control patients, the occurrence of hypercalcemia, severe bone pain, and impending fracture decreased by 65%, 30%, and 50%, respectively. The effect was dose dependent; unfortunately, there was a 23% drop-out rate due to severe gastrointestinal toxicity.
Subsequent investigations have focused mainly on the intravenous administration of pamidronate as palliative treatment. The results of two combined prospective, placebo-controlled, randomized clinical trials of intravenous pamidronate in patients with osteolytic bone metastases have been recently published by Hortobagyi et al. Women with stage IV breast carcinoma who were receiving cytotoxic chemotherapy (380 patients) or endocrine therapy (371 patients) and who had at least one lytic bone lesion were given either 90 mg of pamidronate during a 2-hour infusion monthly for two years or a placebo infusion. After the results of the two studies were pooled, data from 367 patients treated with pamidronate and 384 patients given placebo were available for analysis. The proportion of patients with any skeletal complications was significantly less in the pamidronate group than in the placebo group at 15, 18, 21, and 24 months (P<0.001). In particular, the skeletal morbidity rate (the number of complications per year) at 24 months was 2.4 for the pamidronate group and 3.7 for the placebo group (P=0.001). The median time to the first skeletal complication was 13.9 months in the pamidronate group and 7.0 months in the placebo group. The time of first fracture was increased from 12.8 to 25.2 months. Pain and analgesic use were also decreased among the pamidronate patients. There was no survival difference between the two groups. Furthermore, treatment with pamidronate did not prevent progression of disease in the bone compared with the placebo. Interestingly, when the two studies were analyzed separately, the reduction in skeletal-related events appeared more evident in the group of patients receiving cytotoxic chemotherapy (65% vs 46% for the placebo group) than for the group treated with hormonotherapy (67% vs 56%). The reasons for the differences are not known at this time, but these results may suggest a synergistic antitumor effect between bisphosphonates and chemotherapy that requires further investigation.
Numerous attempts have been made in recent years to better define the biologic modifications associated with bisphosphonate activity, and a number of biochemical and serum protein markers have been proposed. Excretion of alkaline phosphatase and urinary hydroxyproline has been considered to be a sensitive and specific marker for monitoring disease progression in bone metastasis. Coleman et al have reported the results of an evaluation of serum markers associated with bone resorption. N-telopeptide and c-telopeptide demonstrated the greatest variations in inhibition by bisphosphonates. Considering the low specificity and sensitivity of the present markers, none can be recommended for routine use in clinical practice. Future clinical trials may better define the role of these markers when used alone or in combination with others.
Once the efficacy of bisphosphonates as palliative treatment in metastatic breast cancer is established, the next logical step involves testing the possibility of preventing bone metastasis by using bisphosphonates.
Diel et al recently reported a study involving 302 patients with primary breast cancer and tumor cells in the bone marrow. Patients were randomized to either clodronate treatment at a dose of 1,600 mg/day orally for two years (157 patients) or no therapy and standard follow-up (145 patients). All patients received standard adjuvant treatment. Analysis performed at 36 months of follow-up revealed that clodronate treatment was associated with a statistically significant reduction in the number of recurrences of bone metastasis (12 vs 25 in the clodronate vs no treatment groups, respectively), visceral metastases (13 vs 27), and deaths (6 vs 22). In addition, the average number of bone metastases in clodronate-treated patients was significantly lower than that in the control group.
Preliminary data are now available on a randomized trial conducted by Powles et al, which completed accrual in June 1997 and involved 1,079 patients with breast cancer. Patients were randomized to receive either clodronate 1,600 mg/day orally or placebo. Preliminary data suggest a reduction in bone metastases, particularly for postmenopausal patients. A longer follow-up period will be required to evaluate whether the incidence of bone metastases and eventually visceral metastases was reduced, as suggested by the intriguing results reported by Diel and colleagues.
The use of bisphosphonates for the treatment of osteolytic lesions in the setting of metastatic breast cancer has steadily increased in the last several years. Randomized clinical trials have demonstrated a benefit, particularly for pamidronate-treated patients, with a significant reduction in skeletal-related complications and bone pain and an improvement in quality of life.
Based on these data, patients with osteolytic metastatic breast cancer should be initiated on bisphosphonate treatment as early as possible after diagnosis. Pamidronate given as an intravenous infusion every three or four weeks appears to be the most effective treatment and is associated with fewer side effects. This treatment should be continued for as long as efficacy is demonstrated. Oral bisphosphonates, particularly clodronate, may replace pamidronate with perhaps equivalent results but with less tolerance.
Future trials using a new generation of more potent bisphosphonates -- zoledronate and ibandronate -- may offer more effective palliative options and, when used in the setting of adjuvant treatment, are expected to clarify the role of this class of drugs in the prevention of bone metastasis in patients with breast cancer.
A phase I investigation of zoledronate has recently been completed. Doses of 4 mg and 8 mg given as a short infusion (5 minutes) were well tolerated. Phase II trials are currently in progress. Markers of bone resorption will also be routinely evaluated in treated patients to evaluate the variation in clinical efficacy.
Many questions remain partially unanswered, including a detailed clarification of the molecular targets of bisphosphonates and the mechanism of action by which they affect osteoclast activity. Recent studies show that bisphosphonates promote apoptosis of osteoclasts, but they also can affect tumor cells.[35,36] In the setting of cancer, it is important to establish whether bisphosphonates have antitumor effects and which bisphosphonates are the most effective in this regard. No clinical data are presently available to suggest a possible role of bisphosphonates in the management of osteolytic bone metastases due to other solid tumors.
No significant relationship exists between Dr Cristofanilli and the companies/organizations whose products or services are referenced in this article. Dr Hortobagyi is a consultant to Novartis Pharmaceuticals Corp.
NOTE: from JMCC6(3):241-246, 1999
The authors are Dr. G. Hortobagyi and Dr. Cristofanilli