New agents for bone metastasis

Metastases to osseous structures represent the most common metastatic destination for human breast carcinoma. Conversely, breast cancer is one of the most common sources of bone metastases. Bone metastases produce multiple complications, including pain, pathological fractures, hypercalcemia, and spinal cord compression. Some of these complications are potentially catastrophic and all reduce the quality of life of patients with metastatic breast cancer. Analgesics, orthopedic surgery, and radiotherapy have been considered the only successful approaches to the management of complications of bone metastases prior to the therapeutic development of bis-phosphonates. Research over the past decade expanded our understanding of the metastatic process, including the pathophysiology of bone metastases. Cancer cells play a minor role in the direct process of bone metastases. Rather, cancer cells produce and secrete a variety of growth factors (transforming growth factors ∀ and ∃, epidermal growth factor, granulocyte–macrophage colony-stimulating factor) as well as a number of cytokines (tumor necrosis factor, IL-1 and IL-6, prostaglandins) and parathyroid hormone-related protein (PTHrP), which recruit osteoclast precursors and activate mature osteoclasts. It is the excessive osteoclastic activity, uncoupled from matched osteoblastic activity, that results in excessive bone resorption and bone metastases. Therefore, efforts at interfering with osteoclast activation, maturation and the recruitment of osteoclast precursors have become the main focuses of therapeutic research in the area of bone metastases. A variety of substances have been shown to inhibit osteoclast activity; calcitonins, gallium nitrate and bisphosphonates have marked therapeutic effects in the management of hypercalcemia of malignancy, Paget's disease of bone, and bone metastases. Bisphosphonates are considered the standard of care for all these indications. Clodronate, pamidronate, ibandronate, and zoledronic acid have all been shown to reduce bone-related events in randomized trials, including fractures, pain, hypercalcemia, and spinal cord compression. In addition, the systematic use of bisphosphonates, especially IV aminobisphosphonates (pamidronate, zoledronic acid), was also shown in placebo-controlled trials to reduce the need for radiotherapy and orthopedic surgery. Therefore, current practice guidelines indicate initiation of monthly intravenous bisphosphonate therapy upon the identification of bone metastases by imaging, regardless of other anticancer treatment being administered. Bisphosphonate therapy should continue indefinitely, with periodic monitoring of renal function. In patients with primary breast cancer, the use of bisphosphonate therapy for prevention of bone metastases is not indicated outside of a clinical trial. There are conflicting results from three, relatively small, randomized trials regarding the clinical utility of adjuvant bisphosphonate therapy. Ongoing and planned randomized trials in the adjuvant setting should determine the contribution, if any, of bisphosphonates to the management of primary breast cancer. In this regard, NSABP B-34 has completed accrual, and results should be available within the next 1–2 years. A different indication for bisphosphonates, independent of the presence or absence of breast cancer, is for management of osteopenia or osteoporosis. National and international guidelines exist for postmenopausal patients, and patients with breast cancer should be monitored and treated for osteoporosis in the same manner. Because some of the anticancer treatments used to manage breast cancer result in premature ovarian ablation or suppression resulting in rapid bone loss, early assessment of bone density in these patients is necessary to determine the role of bisphosphonate therapy to preserve bone strength and density. A clearer understanding of signaling pathways involved in osteoclast activation and uncoupled and unmatched bone resorption associated with malignant tumors has led to the development of several new strategies to manage metastatic bone disease. Osteoprotegerin, and antibodies directed to the ligand or the receptor activator of nuclear factor-κB, have demonstrated substantial activity in inhibiting osteoclast activation, recruitment and differentiation. Phase II and III trials with some of these agents are progressing rapidly. PTHrP is a critical initiating factor in the process of bone resorption and it is produced by a number of malignant tumor cells, including breast cancer. Antibodies against PTHrP are being explored as therapeutic agents in advanced clinical trials. Src inhibitors might have an important role to play in inhibiting osteoclast activation, and several lead compounds are initiating their clinical evaluation alone and in combination with other relevant treatments. The management of bone metastases has benefited enormously by our expanded understanding of basic biological processes related to osteoclast and osteoblast function. These advances will result in improve management of established bone metastases and possibly effective preventive interventions.