A H Paterson1. 1. University of Calgary and Tom Baker Cancer, Alberta, Canada.
Abstract
BACKGROUND: Bisphosphonates (BPs) reduce bone resorption rates by inhibiting osteoclast function, although direct antineoplastic effects and poorly understood effects on bone pain also may occur. Within the family of BPs there are more similarities in pharmacologic effects than differences, although side effect profiles, rates of oral absorption, and potency do differ. Oral clodronate and intravenous pamidronate reduce skeletal complications in patients with bone metastases from breast carcinoma (as well as in myeloma). Uncontrolled trials of prostate carcinoma also suggest clinical benefit. METHODS: Animal studies show that BPs can reduce the rate of development of bone metastases (for example, in Walker 256 carcinoma), but there is little evidence of an effect at nonosseous sites. The hypothesis that the growth of subclinical osseous metastases is augmented by products of bone resorption (a "vicious cycle") and may be diminished by a local reduction of these substances has led to trials of BPs involving patients with no clinical evidence of bone metastases. These trials are critically assessed in this review. RESULTS: In patients with recurrent breast carcinoma but no overt bone metastases, oral clodronate reduced the number of diagnosed bone metastases; but the number of patients who had relapses in bone, though smaller, was not significantly different from the number among patients who took placebo. In a trial of oral pamidronate, no effect was seen, but compliance was a problem because of gastrointestinal side effects. Patients treated for operable breast carcinoma have four or five times the normal rate of vertebral fracture, and BPs do reduce the rate of bone loss. Three adjuvant clodronate trials have been reported. The first, an open-label controlled trial (Diel et al.), showed a reduction in osseous and nonosseous recurrences and an increase in disease free and overall survival with 2 years of clodronate. A second open-label trial (Saarto et al.) of similar size involving lymph node positive breast carcinoma patients showed no effect on the rate of bone metastasis relapse and a deleterious effect on relapse rates of nonosseous metastases with 3 years of clodronate. A third placebo-controlled trial involving 1079 patients reported, in an interim analysis, a reduction in osseous metastases during treatment with 2 years of clodronate, but no effect on nonosseous metastases or survival. CONCLUSIONS: A confirmatory clinical trial is required for two interrelated reasons: 1) scientifically, it is important to demonstrate that an agent that has its dominant effect on a normal tissue cell, the osteoclast, can influence the growth of neoplastic cells; and 2) from the perspective of patient care, it must be unequivocally shown that a reduction in the rate of osseous recurrence translates into an improvement in disease free survival or an improvement in quality of life through reduction of adverse skeletal events. The National Surgical Adjuvant Breast Project has committed to conducting this study and including women with operable breast carcinoma.
BACKGROUND:Bisphosphonates (BPs) reduce bone resorption rates by inhibiting osteoclast function, although direct antineoplastic effects and poorly understood effects on bone pain also may occur. Within the family of BPs there are more similarities in pharmacologic effects than differences, although side effect profiles, rates of oral absorption, and potency do differ. Oral clodronate and intravenous pamidronate reduce skeletal complications in patients with bone metastases from breast carcinoma (as well as in myeloma). Uncontrolled trials of prostate carcinoma also suggest clinical benefit. METHODS: Animal studies show that BPs can reduce the rate of development of bone metastases (for example, in Walker 256 carcinoma), but there is little evidence of an effect at nonosseous sites. The hypothesis that the growth of subclinical osseous metastases is augmented by products of bone resorption (a "vicious cycle") and may be diminished by a local reduction of these substances has led to trials of BPs involving patients with no clinical evidence of bone metastases. These trials are critically assessed in this review. RESULTS: In patients with recurrent breast carcinoma but no overt bone metastases, oral clodronate reduced the number of diagnosed bone metastases; but the number of patients who had relapses in bone, though smaller, was not significantly different from the number among patients who took placebo. In a trial of oral pamidronate, no effect was seen, but compliance was a problem because of gastrointestinal side effects. Patients treated for operable breast carcinoma have four or five times the normal rate of vertebral fracture, and BPs do reduce the rate of bone loss. Three adjuvant clodronate trials have been reported. The first, an open-label controlled trial (Diel et al.), showed a reduction in osseous and nonosseous recurrences and an increase in disease free and overall survival with 2 years of clodronate. A second open-label trial (Saarto et al.) of similar size involving lymph node positive breast carcinomapatients showed no effect on the rate of bone metastasis relapse and a deleterious effect on relapse rates of nonosseous metastases with 3 years of clodronate. A third placebo-controlled trial involving 1079 patients reported, in an interim analysis, a reduction in osseous metastases during treatment with 2 years of clodronate, but no effect on nonosseous metastases or survival. CONCLUSIONS: A confirmatory clinical trial is required for two interrelated reasons: 1) scientifically, it is important to demonstrate that an agent that has its dominant effect on a normal tissue cell, the osteoclast, can influence the growth of neoplastic cells; and 2) from the perspective of patient care, it must be unequivocally shown that a reduction in the rate of osseous recurrence translates into an improvement in disease free survival or an improvement in quality of life through reduction of adverse skeletal events. The National Surgical Adjuvant Breast Project has committed to conducting this study and including women with operable breast carcinoma.