Biology of Bone Metastases

Treatment and Prevention of Bone Metastases

Traditional treatment options for bone metastases include surgery, radiation (both targeted external-beam radiation and systemic radionuclide therapy), chemotherapy, endocrine therapy, and bisphosphonates.^[9] Systemic administration of therapeutic radioisotopes such as strontium-89 and samarium-153 have been shown to safely and effectively palliate painful bone metastases associated with multiple types of malignancies.^[21] There is some suggestion that they may have a tumoricidal effect as well.^[22] However, while the majority of research shows that surgery and radiation can improve quality of life and overall survival, they do not target the underlying pathophysiology of bone disease.

Bisphosphonates

Despite their seeming differences, both osteoblastic and osteolytic metastases are treated with drugs to reduce or block osteoclast activity and inhibit bone resorption. These are not curative treatments; they slow progression of lesions rather than restore bone health.

Bisphosphonates are analogs of pyrophosphates that bind to remodeling bone, inhibiting several components of the bone resorptive process that include promotion of osteoclast apoptosis, inhibition of osteoclast formation, and recruitment. Older bisphosphonates such as clodronate do not contain nitrogen and are metabolized by osteoclasts. Later-generation bisphosphonates, like zoledronic acid and pamidronate, are nitrogen-containing agents that are internalized by the osteoclasts and inhibit their function by inhibiting farnesyl-diphosphonate (FPP) synthase.^[9]

Thus, bisphosphonates act by binding to bone surfaces undergoing remodeling and are internalized by osteoclasts during bone resorption, resulting in inhibition of osteolysis. The inability of bone to regenerate following bisphosphonate therapy supports the in vitro observation that breast cancer cells alter osteoblast function in addition to inhibiting osteoclast activity.^[5] Bisphosphonates are widely used for bone metastases in breast cancer, multiple myeloma, lung cancer, and prostate cancer (which also has a level of osteolytic activity). They have been shown to reduce bone-related skeletal events.

The US Food and Drug Administration (FDA) has approved pamidronate and zoledronic acid specifically for the treatment of bone metastases. However, other bisphosphonates, including ibandronate and clodronate, have been used with similar effects (Table 2 and Table 3). The majority of studies of these drugs are randomized clinical trials using skeletal-related events (SREs) as primary endpoints. In these studies, SREs included bone pain, fractures, need for surgery or radiation for bone symptoms, spinal cord compression, and hypercalcemia. Among other studies, pamidronate has been shown in two large randomized placebo-controlled trials to decrease the skeletal morbidity rate, delay the time to first SRE, and significantly reduce pain.^[23,24] Zoledronic acid has also been shown to delay the time to first SRE, reduce the incidence of SREs, and significantly reduce pain.^[2,25,26] Although not approved in the United States, clodronate and ibandronate are used in other countries and also have been shown to delay the occurrence of new bone events and to decrease pain.^[27–30] The primary side effects associated with bisphosphonate treatment include anemia, gastrointestinal symptoms (eg, nausea, vomiting, diarrhea, or constipation), fatigue, fever, weakness, arthralgias, myalgias and, less commonly, hypocalcemia. Renal toxicity has led to an FDA black box warning to measure creatinine before bisphosphonate administration. Osteonecrosis of the jaw is a recently described complication of bisphosphonate use and is most commonly associated with the amino bisphosphonates. Dental evaluation for patients is recommended.^[31–33]

Other Bone-targeted Therapies

Denosumab is the most recently approved therapy for osseous metastases. It is a fully human monoclonal antibody to RANKL and is a potent inhibitor of osteoclastogenesis and suppression of bone resorption. It has been approved for the treatment of post-menopausal osteoporosis as well as bone metastases from solid tumors and multiple myeloma. A phase II dose-finding study by Lipton et al^[34] studied women with breast cancer- related bone metastases, randomly assigning them to 6 different cohorts, 5 of which included denosumab. The primary endpoint was the change in the bone turnover marker, urine N-telopeptide, corrected for urine creatinine (uNTx/Cr). Safety and SREs were also evaluated. A significantly higher proportion of patients on denosumab demonstrated a reduction in the uNTx/Cr, and significantly fewer patients on denosumab experienced SREs (9% compared to 16% on bisphosphonates). A large, placebo-controlled randomized trial directly compared denosumab to zoledronic acid and found that it was superior in delaying or preventing SREs in patients with breast cancer metastatic to bone.^[35]

Multiple other therapeutic agents are currently being investigated, including antibodies against PTHrP and pharmacologic agents that block PTHrP, which in experimental models block osteolysis.^[36,37] TGF-β is also a potential target, and inhibitors of TGF-β receptor 1 kinase have been shown to reduce the development and progression of osteolytic bone metastases through a variety of downstream effects.^[38] Cathepsin K is a molecule that is produced by metastatic cancer cells and is involved in osteoclast-mediated bone degradation. In preclinical models, inhibitors of cathepsin K have been shown to reduce tumor burden in breast cancer metastatic to bone. A recent double-blind, randomized controlled trial reported by Jensen et al^[39] showed that odanacatib, a cathepsin K inhibitor, suppressed uNTx similarly to zoledronic acid and was safely tolerated. PSK 1404, an antagonist of alpha vB3 integrin, an adhesion receptor implicated in tumor cell invasion and osteoclast-mediated bone resorption, has also been shown in preclinical models to reduce bone destruction and skeletal tumor burden.^[40] The ET-1 receptor is also a potential for targeted therapy; preclinical data involving ETAR antagonists that inhibit the ET-1 signaling pathway have been shown to reduce tumor burden and bone lesions.^[41] Atrasentan is an ETAR antagonist that has been shown to delay progression of osteoblastic skeletal metastases in men with advanced prostate cancer. ^[18,42] ZD4054, or zibotentan, is another ETAR antagonist that is currently in clinical trials. Another possible target is the suppression of endogenous antagonists of the Wnt signaling pathway, suppressing antagonists such as DKK1 and sclerostin. The antibody BHQ880 is a fully human monoclonal antibody that promotes osteoblastogenesis.^[20] Several drugs currently used in the treatment of multiple myeloma, including the proteosome inhibitor bortezomib and immunomodulatory drugs lenalidomide and pomalidomide, are being investigated further as they have been shown to inhibit osteoclastogenesis in vitro and to decrease the RANKL/OPG ratio in patient serum.^[43,44] As the common and disease-specific pathways involved in bone metastases are further elucidated, more targets will become available to intervene clinically.

Cancer Control. 2012;19(2):92-101. © 2012 H. Lee Moffitt Cancer Center and Research Institute, Inc.
Copyright by H. Lee Moffitt Cancer Center & Research Institute. All rights reserved.