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Background: Bisphosphonates have been used successfully in the treatment of hypercalcemia and to reduce skeletal complications of bone metastasis, but have not been shown to prevent bone metastasis or to prolong survival time in metastatic breast cancer patients. The aim of this study was to determine whether the progression-free survival (PFS) and overall survival (OS) of patients with bone-only breast cancer metastasis differed based on whether patients received zoledronic acid, pamidronate, or no bisphosphonate upon diagnosis of their metastases., Patients and Methods: We retrospectively identified 314 patients diagnosed with bone-only metastasis at the time of initial staging or who developed bone metastasis as the first recurrence site during follow-up from January 1, 1997 to December 31, 2008, at The MD Anderson Cancer Center. Univariate and multivariate Cox hazards models were used to assess the effects of each treatment on PFS and OS., Results: Patients who had more than 1 bone metastasis and Eastern Cooperative Oncology Group (ECOG) performance status of 2 and 3 were more likely to receive zoledronic acid in this analysis. Compared with no bisphosphonate use, the use of zoledronic acid was not significantly associated with longer PFS (hazard ratio [HR] = 0.72, P = .058 in univariate analysis, and HR = 0.80, P = .235 in multivariate analysis) nor with longer OS (HR = 1.04, P = .863 in univariate analysis and HR = 1.34, P = .192 in multivariate analysis)., Conclusion: Our study demonstrates that for patients with bone-only metastases, zoledronic acid did not prolong PFS or OS. In patients with bone-only metastasis, we could not demonstrate antitumor effects of zoledronic acid., (Copyright © 2011 American Cancer Society.)

Bone is the most common metastatic site for breast cancer, and bone metastases can cause pain as well as risk of pathological fractures. Emerging treatments for metastatic bone disease have arisen from advances in our understanding of the unique cellular and molecular mechanisms that contribute to bone metastasis. The interaction between tumor cells and the bone microenvironment results in a 'vicious cycle' that increases both bone destruction and tumor burden. The tumor secretes factors, such as parathyroid hormone-related peptide, that stimulate osteoclastogenesis. Similarly, the bone stroma produces growth factors, such as transforming growth factor β, that promote tumor growth in bone. Therapeutic targeting of these microenvironmental factors is under intensive investigation. Other attractive therapeutic targets include signaling molecules, such as receptor activator of nuclear factor κB ligand, Src kinase, and cathepsin K, all of which regulate osteoclast function, and chemokine receptor 4, which is involved in the homing of tumor cells to bone. In this Review, we describe the progress and future directions of novel bone-targeted therapies that may reduce or prevent destructive bone metastasis from breast cancer. Novel modalities for predicting and monitoring treatment response will also be described.

Purpose of Review: To describe recent data on the effects of bisphosphonates on bone health for patients with primary breast cancer., Recent Findings: Data are accumulating regarding the salutary effect of bisphosphonates on bone health. Preservation of bone mineral density, a surrogate for fracture risk, has been demonstrated in randomized controlled trials of bisphosphonates. These trials have included premenopausal and postmenopausal women and endocrine and chemotherapy adjuvant breast cancer treatments. In these trials there has been a focus on gonadal dysfunction, use of aromatase inhibitors and the risk of osteopenia/osteoporosis. Data with bisphosphonates in this clinical setting have not confirmed clinical benefit for fracture risk.Adjuvant studies to assess the prevention of bone metastases have appropriate scientific rationale, including the potential antitumor effects of bisphosphonates, but large randomized controlled trials are incomplete., Summary: The use of a bisphosphonate is warranted for preservation of bone mineral density in women with primary breast cancer and gonadal dysfunction or drug-induced hypoestrogenism. The potential additional benefit of delay or prevention of bone metastasis awaits confirmation from randomized controlled trials.Expert consensus panels have suggested guidelines for use of bisphosphonates for prevention of cancer treatment induced bone loss.

Treatment-induced osteoporosis is an increasing problem for women diagnosed with breast cancer. As more women receive adjuvant endocrine therapy and chemotherapy, and breast cancer survival improves, the impact of cancer treatment on bone health and the morbidity associated with chemotherapy-induced bone loss becomes more of a significant medical concern. Endocrine agents like aromatase inhibitors and luteinizing hormone-releasing hormone agonists decrease the production of ovarian and adrenal estrogens and are widely used in the adjuvant and metastatic settings for treatment of women with hormone receptor-positive breast cancer. Estrogen is important for bone health. It stimulates osteoblasts and maintains bone integrity. As bone density decreases, the risk of fracture increases. This can include fractures of the wrist, femur, and vertebrae. Several potent bisphosphonates have been developed to prevent or treat cancer treatment-induced bone loss.

Zoledronic acid (Zometa) is the most recent addition to the clinically available bisphosphonates. Clinical benefits in metabolic, as well as cancer-related bone disease have been observed. In addition to its profound antiosteoclast effects, it has demonstrated anticancer effects in preclinical models. Zoledronic acid has been evaluated in randomized, double-blind clinical trials of osteoporosis, Paget's disease of bone, and metastatic, osteolytic and osteoblastic bone disease. Antiosteoclast activity has been demonstrated by reductions in the bone breakdown products N-telopeptide, C-telopeptide and deoxypyridinoline. Bone mineral density, measured by dual energy x-ray absorptometry, is increased with administration of zoledronic acid in postmenopausal osteoporosis. Clinical benefit in cancer includes improvement in bone pain, reductions in skeletal events and delay in time-to-first-skeletal-events. These zoledronic acid treatment benefits have been demonstrated in patients with multiple myeloma, breast, prostate and lung cancer, and other solid tumors.

Breast cancer frequently metastasizes to bone. Metastases result in skeletal morbidity including pathologic fractures, the need for radiation or surgery to bone, spinal cord compression and hypercalcemia. The pathophysiology of bone destruction is related to activation of osteoclasts by tumor-derived and bone marrow microenvironmental factors. One prominent osteoclast-activating factor associated with breast cancer is parathyroid hormone-related peptide (PTHrP). Bisphosphonates have been shown to impair osteoclast activity by decreasing recruitment from the monocyte macrophage cell line, inhibiting osteoclast function at the bone site and causing osteoclasts to undergo apoptosis. Clinical studies with bisphosphonates show an improvement in the control of hypercalcemia and a reduction in skeletal related morbidity with administration of pamidronate and zoledronic acid. Bisphosphonates have become the standard of care for osteolytic metastases associated with breast cancer. Recent data with zoledronic acid found that skeletal related morbidity may be reduced regardless of the radiographic picture of skeletal metastases. Thus, zoledronic acid may be valuable in osteolytic and osteoblastic disease as well as in disease with an osteolytic or osteoblastic radiographic appearance. In breast cancer with osteolytic disease, zoledronic acid may be more effective than pamidronate in reducing skeletal morbidity and prolonging the time to first skeletal event.

Bisphosphonates, analogs of pyrophosphate, bind to bone at sites of active bone remodeling. In clinical settings of rapid bone turnover and/or excessive osteolytic activity, they have been shown to have beneficial clinical effects. These settings include Paget's disease of bone, osteoporosis from a variety of clinical causes, and malignant bone disease. Bisphosphonate inhibition of osteolysis in cancer has been shown to be effective therapy for malignancy-associated hypercalcemia and as adjunctive therapy for the delay or prevention of cancer-related skeletal morbidity, including bone pain, pathologic fractures, and need for radiation therapy. Animal models of bone metastasis prevention by bisphosphonate treatment have provided the preclinical background for the adjuvant use of bisphosphonates in primary cancers. The success of these clinical trials has provided strong impetus for new research on bone disease and malignancy, as well as the development and testing of new and more potent bisphosphonates. Semin Oncol 28:284-290., (Copyright 2001 by W.B. Saunders Company.)

Background: Pamidronate therapy previously has been shown to reduce skeletal complications effectively for up to 12 months in breast carcinoma patients with bone metastases. The current study data provide further follow-up results regarding the effects of long term (up to 24 months) pamidronate treatment in women with breast carcinoma and osteolytic metastases., Methods: Follow-up results from two prospective, multicenter, randomized, double-blind, placebo-controlled intervention trials conducted at academic and community oncology centers were combined to provide a large data set with which to evaluate the long term efficacy and safety of pamidronate therapy. Seven hundred fifty-four women with Stage IV breast carcinoma and osteolytic metastases were randomized to the 2 treatment arms of the trial. Three patients were excluded from the intent-to-treat population for the analysis. A total of 751 evaluable patients were randomized to receive either a 90-mg intravenous pamidronate infusion (367 patients) or a placebo infusion (384 patients) every 3-4 weeks. The primary outcome measures were skeletal morbidity rate (events/year), proportion of patients developing a skeletal complication, and time to first skeletal complication., Results: Of the 367 women receiving pamidronate, 115 (31.3%) completed the trial and 81 (22.1%) discontinued the study due to adverse events. Of the 384 women who received placebo, 100 (26.0%) completed the study and 76 (19.8%) discontinued the study due to adverse events. The skeletal morbidity rate was 2.4 in the pamidronate group and 3.7 in the placebo group (P < 0.001). In the pamidronate group, 186 of the 367 patients (51%) had skeletal complications compared with 246 of the 384 patients in the placebo group (64%) (P < 0.001). The median time to first skeletal complication was 12.7 months in the pamidronate group and 7 months in the placebo group (P < 0.001). Six patients treated with pamidronate discontinued treatment due to drug-related adverse events. Pain and analgesic scores were significantly worse in the placebo group compared with those patients in the pamidronate group., Conclusions: In the current study, monthly infusions of 90 mg of pamidronate as a supplement to antineoplastic therapy were found to be well tolerated and superior to antineoplastic therapy alone in preventing skeletal complications and palliating symptoms for at least 24 months in breast carcinoma patients with osteolytic bone metastases., (Copyright 2000 American Cancer Society.)

Purpose: To assess whether pamidronate can reduce the frequency of skeletal morbidity in women with lytic bone metastases from breast cancer treated with hormone therapy., Patients and Methods: Three hundred seventy-two women with breast cancer who had at least one lytic bone lesion and who were receiving hormonal therapy were randomized to receive 90 mg of pamidronate or placebo as a 2-hour intravenous infusion given in double-blind fashion every 4 weeks for 24 cycles. Patients were evaluated for skeletal complications: pathologic fractures, spinal cord compression, irradiation of or surgery on bone, or hypercalcemia. The skeletal morbidity rate (the ratio of the number of skeletal complications to the time on trial) was the primary efficacy variable. Bone pain, use of analgesics, quality of life, performance status, bone tumor response, and biochemical parameters were also evaluated., Results: One hundred eighty-two patients who received pamidronate and 189 who received placebo were assessable. The skeletal morbidity rate was significantly reduced at 12, 18, and 24 cycles in patients treated with 90 mg of pamidronate (P = .028, .023, and .008, respectively). At 24 cycles, the proportion of patients having had any skeletal complication was 56% in the pamidronate group and 67% in the placebo group (P = .027). The time to the first skeletal complication was longer for patients receiving pamidronate than for those given placebo (P = .049). There was no statistical difference in survival or in objective bone response rate. Pamidronate was well tolerated., Conclusion: Treatment with 90 mg of pamidronate as a 2-hour intravenous infusion every 4 weeks in addition to hormonal therapy significantly reduces skeletal morbidity from osteolytic metastases.

Purpose: Pamidronate, an aminobisphosphonate, has been shown to lower the risk of skeletal complications associated with lytic bone lesions for up to 1 year in women with stage IV breast cancer who received chemotherapy. We studied the long-term effectiveness and safety of continued treatment with intravenous pamidronate infusions for up to 2 years., Patients and Methods: Three hundred eighty-two women with metastatic breast cancer and lytic bone lesions who received chemotherapy were randomly assigned to receive either 90 mg of pamidronate or placebo intravenously every 3 to 4 weeks in this double-blind, multicenter, parallel-group trial. Patients were evaluated monthly for 2 years for skeletal complications, which included pathologic fractures, need for radiation or surgery to treat bone complications, spinal cord compression, and hypercalcemia. Bone pain, analgesic use, bone biochemical markers, performance status, quality of life, radiologic response in bone, and survival were also evaluated., Results: As in the first year of treatment, the proportion of patients with any skeletal complication was significantly less for the pamidronate than the placebo group at 15, 18, 21, and 24 months (P < .001). The proportions of patients with any pathologic fracture (i.e., vertebral and nonvertebral fractures), need for radiation or surgery to treat bone complications, and hypercalcemia were also statistically less for the pamidronate than the placebo group. The median time to the first skeletal complication was 13.9 months in the pamidronate-treated women and 7.0 months in the placebo group (P < .001). Long-term treatment did not result in any unexpected adverse events. Survival did not differ between the two groups., Conclusion: The risk for osteolytic bone lesion complications in metastatic breast cancer was significantly decreased with monthly infusions of 90 mg of pamidronate, and this effect was maintained for at least 2 years. Pamidronate is a useful adjunct to standard chemotherapy in the palliative treatment of metastatic breast cancer.

At M. D. Anderson, the use of the recently approved bisphosphonate pamidronate (Aredia) became a part of the standard of care pathway for the treatment of osteolytic metastases from breast cancer. How any agent achieves that status involves the long process of completing clinical trials and resolving many practical and ethical dilemmas. What criteria determine the standard of care and who decides what those criteria should be are two of the many questions that need to be answered before a treatment modality or specific agent becomes part of the standard of care. This article describes how pamidronate achieved that status at M. D. Anderson.

Background: Bisphosphonates such as pamidronate disodium inhibit osteoclast-induced bone resorption associated with cancer that has metastasized to bone., Methods: Women with stage IV breast cancer who were receiving cytotoxic chemotherapy and had at least one lytic bone lesion were given either placebo or pamidronate (90 mg) as a two-hour intravenous infusion monthly for 12 cycles. Skeletal complications, including pathologic fractures, the need for radiation to bone or bone surgery, spinal cord compression, and hypercalcemia (a serum calcium concentration above 12 mg per deciliter [3.0 mmol per liter] or elevated to any degree and requiring treatment), were assessed monthly. Bone pain, use of analgesic drugs, performance status, and quality of life were assessed throughout the trial., Results: The efficacy of treatment was evaluated in 380 of 382 randomized patients, 185 receiving pamidronate and 195 receiving placebo. The median time to the occurrence of the first skeletal complication was greater in the pamidronate group than in the placebo group (13.1 vs. 7.0 months, P=0.005), and the proportion of patients in whom any skeletal complication occurred was lower (43 percent vs. 56 percent, P = 0.008). There was significantly less increase in bone pain (P=0.046) and deterioration of performance status (P=0.027) in the pamidronate group than in the placebo group. Pamidronate was well tolerated., Conclusions: Monthly infusions of pamidronate as a supplement to chemotherapy can protect against skeletal complications in women with stage IV breast cancer who have osteolytic bone metastases.