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© 2001 American Society for Clinical Oncology Safety and Efficacy of Bisphosphonates Beyond 24 Months in Cancer PatientsByFrom the M.S. Hershey Medical Center, Hershey, PA. Address reprint requests to Allan Lipton, MD, Division of Hematology/Medical Oncology, 500 University Dr, PO Box 850, HO46, Hershey, PA 17033; email: alipton{at}psu.edu
PURPOSE: Bisphosphonate therapy has decreased the risk of skeletal complications associated with osteolytic bone lesions in patients with breast cancer and multiple myeloma. The large prospective studies have used 21 to 24 months of treatment. We studied the safety and efficacy of bisphosphonates in a subset of patients who received therapy for more than 24 months. PATIENTS AND METHODS: Patients who received bisphosphonates (pamidronate or zoledronic acid) were identified. Data on skeletal events and laboratory parameters were gathered by chart review. RESULTS: We studied 22 patients who received intravenous pamidronate or zoledronic acid for a duration of 3.6 years (range, 2.2 to 6.0 years). Prolonged therapy was well tolerated. No significant calcium, phosphorus, electrolyte, or WBC count abnormalities were encountered. There was a clinically insignificant decrease in hemoglobin and platelet count and an increase in creatinine in these patients. The fracture rate beyond 2 years was no greater than during the first 2 years of treatment. There were no stress fractures of long bones with prolonged therapy. CONCLUSION: Prolonged treatment with the potent bisphosphonates pamidronate and zoledronic acid seems to be well tolerated and should be studied in prospective, randomized studies to document prolonged skeletal efficacy.
TREATMENT WITH bisphosphonates has been shown to decrease the risk of skeletal complications and pain associated with osteolytic bone lesions in patients with breast cancer and multiple myeloma. Two multicenter, randomized, double-blind, placebo-controlled trials of pamidronate have been reported in patients with stage IV breast cancer. Patients received either 90 mg of pamidronate or placebo given as a 2-hour intravenous (IV) infusion every 3 to 4 weeks for 2 years. The study population consisted of 754 patients, 367 in the pamidronate group and 387 in the placebo group. Overall, 31.3% of the pamidronate and 25.8% of placebo patients completed the 24 months of treatment. The number of skeletal complications over time was reduced by 35% in the pamidronate group compared with the placebo group, and 20% fewer pamidronate-treated patients experienced any of the skeletal complications commonly associated with metastatic bone disease.1-3 Furthermore, the time to a first skeletal complication was significantly longer in the pamidronate-treated group than in the placebo-treated group. Similar results have been obtained in patients with Durie-Salmon stage III multiple myeloma in whom 21 months of IV pamidronate resulted in a one-third reduction in the number of skeletal-related events.4 The skeletal half-life of bisphosphonates is long. This accumulation of a bisphosphonate in bone does not, however, lead to cumulative effects on bone metabolism. In patients with osteoporosis, the sustained suppression of bone turnover induced by long-term treatment with pamidronate is readily reversible by stopping treatment.5 In one osteoporosis study, the suppression of bone turnover using oral pamidronate was reversible within 6 months of stopping treatment.6 In patients with osteolytic bone metastases, markers of bone resorption returned to pretreatment values within 4 weeks of an IV dose of pamidronate.7 Treatment of osteolytic disease in breast cancer and multiple myeloma patients with IV pamidronate has gained widespread acceptance over the past decade. A question frequently encountered by the treating physician is how long to continue treatment. Studies of etidronate (Didronel; Taylor Pharmaceuticals Company, Decatur, IL), a first-generation bisphosphonate, demonstrated inhibition of normal skeletal mineralization and fractures. Compared with etidronate, pamidronate and zoledronic acid are 100-fold and 1,000-fold more potent, respectively, in inhibiting osteoclast activity.8 The potency facilitates a dose of zoledronic acid of 4 mg administered over a 15-minute infusion. This agent, Zometa (zoledronic acid for injection; Novartis Pharmaceutical Corporation, East Hanover, NJ) currently is being studied in large randomized trials in bone metastases associated with a variety of tumor types. These agents are potent inhibitors of bone resorption at doses that do not effect bone mineralization. There are no data observing cancer patients receiving bisphosphonate therapy beyond 2 years. The available data for use of a second-generation bisphosphonate in cancer patients are for a duration of 2 years. The potential benefits and toxicities of continuing bisphosphonate therapy for a longer period have not been studied. In this study, we addressed the questions of the pattern of adverse skeletal events and changes in laboratory parameters occurring in oncology patients receiving either IV pamidronate or zoledronic acid for longer than 2 years.
Patients Patients included in this study were treated at the M.S. Hershey Medical Center, Hershey, PA, and M.D. Anderson Cancer Center, Houston, TX. Twenty-two patients who received either pamidronate or zoledronic acid for longer than 2 years were evaluated. Breast cancer patients had stage IV disease and at least one predominantly lytic metastatic bone lesion measuring at least 1 cm in diameter. They received hormonal therapy or chemotherapy according to the treatment protocol. Similarly, stage III multiple myeloma patients with at least one lytic lesion were included. Patients were ineligible for these studies if they had a skeletal-related event within 2 weeks before enrollment, had radiation therapy during 2 weeks before trial, or received bisphosphonates within 60 days before enrollment.
Treatment
Laboratory Tests
Twenty-two patients received more than 2 years of bisphosphonate therapy. Mean duration of follow-up was 3.6 years (range, 2.2 to 6.0 years). The mean age of the patients was 53 years. The patients included five men with multiple myeloma and 17 women with breast cancer. Eighteen patients were treated with pamidronate, and four received zoledronic acid. During their first 2 years of treatment with either pamidronate or zoledronic acid, six of 22 patients developed a pathologic fracture or received radiation therapy. The treatment protocol allowed physicians to continue to treat patients with bisphosphonate therapy if in their assessment the patient was benefiting from therapy. Skeletal surveys performed at the end of the bisphosphonate study showed partial response in two patients (9%), stable disease in three patients (14%), mixed progression in 10 patients (45%), and progression in three patients (14%). Results of a skeletal survey at the end of study were not available for four patients (18%). The results of a 2-year skeletal survey and the skeletal-related events are described in Table 1. The changes in the skeletal survey did not necessarily predict the occurrence of fracture or the need for radiation therapy.
Four of these 22 patients who continued bisphosphonate treatment beyond 2 years experienced a fracture. Skeletal events that occurred after the first 2 years of bisphosphonate treatment were as follows: (1) stress fracture in the region of a hip prosthesis, (2) traumatic fracture of the big toe, (3) compression fracture of the base of the skull, and (4) compression fracture of a thoracic vertebra. A Kaplan-Meier plot of the incidence of fracture during the first 2 years, and longer, of bisphosphonate therapy is presented in Fig 1.
There were no clinically relevant changes in complete blood cell counts, platelet counts, calcium analyses, electrolyte analyses, or kidney function tests for these patients receiving long-term bisphosphonate treatment. The last laboratory values were determined at a mean of 3.5 years (range, 1.7 to 6 years). Hematocrit decreased by 10% from 36.9% to 33.6%, platelet count decreased by 30% from 232 to 156 k/mm3, and creatinine increased by 16% from 0.9 to 1.1 mg/dL (Table 2).
The reasons for stopping bisphosphonate treatment are presented in Table 3. Eight patients stopped treatment due to extensive disease progression or death, two patients requested to stop treatment for personal reasons, and two patients were lost to follow-up and are presumed to have died. Ten patients continue to receive monthly bisphosphonate therapy.
During the past decade there has been widespread acceptance of the use of bisphosphonates in addition to chemotherapy or hormone therapy for breast cancer and multiple myeloma patients with osteolytic bone metastases. The trials that led to this change in clinical practice were large, multicenter, randomized, double-blind, placebo-controlled trials that had the same design and end points. All patients had x-ray evidence of osteolytic bone metastases. In addition to systemic therapy of the underlying disease, patients with multiple myeloma received 90 mg of pamidronate every 4 weeks for 21 months, and breast cancer patients received 24 months of therapy. To date there are no data as to either long-term efficacy or toxicity of bisphosphonate therapy. In this report we evaluated 22 patients who continued to receive either pamidronate sodium or the third-generation bisphosphate zoledronic acid beyond 2 years. The mean duration of therapy was 3.6 years (range, 2.2 to 6 years). The rationale for continued treatment was based on the rapid reversal of suppression of bone turnover upon cessation of bisphosphonate treatment in patients with either osteoporosis or osteolytic bone metastases.5-7 Treatment with the first-generation bisphosphonate etidronate resulted in impaired mineralization of bone. In patients with Paget’s disease, stress fractures were seen in the lower extremities.9 Stress fractures of the lower extremities have also been described in patients with osteoporosis who were treated with etidronate.10 There are extensive animal data evaluating the effect of second- and third-generation bisphosphonates on bone mineralization. A study in dogs has shown the administration of pamidronate for 1 year results in an increase in bone mineralization.11 Increase in bone mineral density after 6 months was seen in a pilot trial of patients with multiple myeloma being treated with pamidronate.12 In patients with multiple myeloma treated with oral pamidronate for a median of 27.5 months, there was no sign of impaired osteoblast function or mineralization defect.13 In this study, patients experienced six fractures during the first 2 years of bisphosphonate therapy, and only four fractures occurred beyond 2 years. There were no stress fractures of long bones. One of the fractures was of the big toe and another stress fracture was in the region of a previous hip prosthesis—both possibly unrelated to the underlying malignancy. The fracture rate beyond 2 years of therapy was no greater than the fracture rate during the first 2 years in this small cohort. Prolonged treatment with a potent bisphosphonate has not resulted in significant biochemical abnormalities. No electrolyte or calcium problems have been encountered. Slight decreases in hematocrit and platelet count and an increase in creatinine have not caused significant clinical problems. A similar slight decrease in hematocrit was also noted more often in the patients receiving pamidronate in the large randomized myeloma study at the end of 2 years, but there was no difference in the number of transfusions or use of erythropoietin in the two groups.4 Also, many of these patients had progressive disease and received many different therapies. As has been seen in previous studies, many patients receiving bisphosphonates have progressive disease in extraskeletal sites.1-3 However, almost half of our patients continue to receive prolonged bisphosphonate treatment due to stable bone disease. In summary, IV pamidronate or zoledronic acid can be safely administered for more than 2 years to improve quality of life in cancer patients with osteolytic disease. Randomized studies should be performed to document the continued benefit of bisphosphonates on the skeleton with therapy continuing beyond 2 years.
1. Hortobagyi GN, Theriault RL, Lipton A, et al: Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate: Protocol 19 Aredia Breast Cancer Study Group. J Clin Oncol 16: 2038-2044, 1998[Abstract]
2.
Theriault RL, Lipton A, Hortobagyi GN, et al: Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: A randomized, placebo-controlled trial—Protocol 18 Aredia Breast Cancer Study Group. J Clin Oncol 17: 846-854, 1999 3. Lipton A, Theriault RL, Hortobagyi GN, et al: Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: Long term follow-up of two randomized, placebo-controlled trials. Cancer 88: 1082-1090, 2000[Medline] 4. Berenson JR, Lichtenstein A, Porter L, et al: Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events: Myeloma Aredia Study Group. J Clin Oncol 16: 593-602, 1998[Abstract]
5.
Ravn P, Bidstrup M, Wasnich RD, et al: Alendronate and estrogen-progestin in the long-term prevention of bone loss: Four-year results from the early postmenopausal intervention cohort study. Ann Intern Med 131: 935-942, 1999 6. Landman JO, Hamdy NAT, Pauwels EKJ, et al: Skeletal metabolism in patients with osteoporosis after discontinuation of long-term treatment with oral pamidronate. J Clin Endocrinol Metab 80: 3465-3468, 1995[Abstract] 7. Lipton A, Demers L, Curley E, et al: Markers of bone resorption in patients treated with pamidronate. Eur J Cancer 34: 2021-2026, 1998
8.
Fleisch H: Bisphosphonates: Mechanisms of action. Endocr Rev 19: 80-100, 1998 9. Boyce BF, Smith L, Fogelman I, et al: Focal osteomalacia due to low-dose diphosphonate therapy in Paget’s disease. Lancet 1: 821-824, 1984[Medline] 10. Guanabens N, Peris P, Monegal A, et al: Lower extremity stress fractures during intermittent cyclical etidronate treatment for osteoporosis. Calcif Tissue Int 54: 431-434, 1994[Medline] 11. Grynpas MD, Acito A, Dimitriu M, et al: Changes in bone mineralization, architecture and mechanical properties due to long-term (1 year) administration of pamidronate (APD) to adult dogs. Osteoporos Int 2: 74-81, 1992[Medline] 12. Berenson J, Webb I, Anderson K, et al: A phase II dose ranging trial of single-agent pamidronate for relapsed or refractory multiple myeloma. Cancer 88: 3101, 2000 (abstr, suppl) 13. Abildgaard N, Rungby J, Glerup H, et al: Long-term oral pamidronate treatment inhibits osteoclastic bone resorption and bone turnover without affecting osteoblastic function in multiple myeloma. Eur J Haematol 61: 128-134, 1998[Medline] Submitted October 16, 2000; accepted April 17, 2001. This article has been cited by other articles:
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
