The skeleton is the most common site of metastases in patients with epithelial malignancies. Worldwide, it is estimated that 1.5 million patients with cancer have bone metastases. In the U.S. alone, approximately 400,000 patients are diagnosed with bone metastases annually.
Bone metastases are commonly associated with breast, prostate, lung, and renal cancers. Postmortem examinations of patients dying of cancer confirm that 75 percent of patients with breast or prostate cancer and nearly 40 percent of patients with lung and renal cancers have evidence of metastatic bone disease. Common sites of bone metastases are the ribs, spine, pelvis, skull, and proximal limbs.
Apart from hypercalcemia, patients with bone metastases are also at risk for potentially debilitating skeletal-related events (SREs). Those associated with bone metastases include pathologic fracture, use of palliative radiation therapy, need for surgery to bone to treat or prevent an impending pathologic fracture, and spinal cord compression.
Approximately two-thirds of patients with malignant bone lesions develop at least one SRE if they do not receive bone-directed therapy. Although the rate of SREs is highly variable, patients generally experience a larger number of SREs as their disease progresses. Moreover, patients who have one SRE are at increased risk for subsequent SREs.
Patients with metastatic bone disease live for a significant time after their first SRE. Cancer patients who experience a pathologic fracture are at significantly increased risk of death in the next 12 months compared with patients who do not experience a pathologic fracture.
Healthy bone is in a state of equilibrium in which the processes of bone deposition and bone resorption are normally balanced. In normal bone development, remodeling is an ongoing and ordered process regulated by two different cell types with opposing functions: osteoclasts, which resorb bone; and osteoblasts, which deposit bone.
The interaction of receptor activator of nuclear factor kappa B ligand (RANKL) with the RANK receptor is pivotal for the regulation of osteoclast-mediated bone resorption during normal bone remodeling. The binding of RANKL to its receptor, RANK, activates downstream signaling pathways that drive the differentiation, survival, and function of osteoclasts. The interaction of RANKL and RANK is blocked by osteoprotegerin (OPG), an endogenous decoy receptor of RANKL, secreted by osteoblasts. By interfering with the interaction of RANKL/RANK, OPG limits osteoclastogenesis, resulting in an increase in bone density.
At the site of bone metastases there is locally increased bone remodeling and increased osteoclast activity. The “vicious cycle” hypothesizes that tumor cells interact with the bone marrow microenvironment to drive bone destruction and tumor growth in a symbiotic relationship. The tumor cells secrete various factors that stimulate production of RANKL. In turn, the increased expression of RANKL in the tumor environment leads to increased formation, activation, and survival of osteoclasts and resulting osteolytic lesions. Osteolysis then leads to the release of growth factors derived from bone (e.g., TGF-beta) and these factors promote tumor growth.
Bisphosphonates have a high affinity for bone and readily bind to bone. After binding, bisphosphonates are taken up by actively resorbing osteoclasts. The bisphosphonate induces apoptosis of osteoclasts by inhibition of key pathways for osteoclast survival. Multiple studies have demonstrated the efficacy of several bisphosphonates in patients with metastatic bone disease.
Two potent, nitrogen-containing bisphosphonates are approved for the treatment of bone metastases. Pamidronate, first approved on the basis of two placebo-controlled trials, shown to reduce skeletal complications in patients with breast cancer and SREs in patients with multiple myeloma.
Zoledronic acid was evaluated in a head-to-head comparative trial versus pamidronate in patients with breast cancer or multiple myeloma. The primary endpoint was the proportion of patients with at least one SRE, and zoledronic acid was found to be non-inferior to pamidronate for this endpoint.
Analyses of protocol-defined patient strata revealed that in breast cancer patients receiving hormonal therapy, treatment with zoledronic acid significantly prolonged the time to first SRE (415 days) compared with pamidronate (370 days). In this patient population, zoledronic acid reduced the skeletal morbidity rate from 1.37 to 0.83 SREs/year, and the risk of developing any SRE, including hypercalcemia, by an additional 20 percent versus pamidronate in exploratory multiple event analyses in the subset of patients with breast cancer.
Phase III trials of zoledronic acid vs. placebo were also conducted in prostate cancer and other solid tumors (excluding breast and prostate cancer). In both studies, zoledronic acid decreased the risk for all types of SREs, as well as reducing the skeletal morbidity. Also, in both studies zoledronic acid significantly delayed the time to first SRE.
Despite the availability of bisphosphonates, approximately 40 percent of patients with bone metastases continue to experience skeletal complications. Bisphosphonates have also been associated with deterioration of renal function.
Denosumab is a fully human monoclonal antibody to RANKL, the key mediator of osteoclast formation, function, and survival. In patients with bone metastases denosumab (at 120 mg) is administered as a single subcutaneous injection once every four weeks. As denosumab is a fully human monoclonal antibody, it is cleared via the reticuloendothelial system and does not require renal monitoring.
Denosumab was directly compared with zoledronic acid in three identically designed Phase III trials. Results from the breast cancer trial showed that denosumab was superior to zoledronic acid in delaying both the time to a first on-study SRE as well as the time to a first-or-subsequent SRE. Similar results were also observed in the prostate cancer trial and in the other solid tumor trial (not including the myeloma patients).
The identical design of these three trials allowed the patient level data to be combined to assess the efficacy of denosumab across a broad range of tumor types. Denosumab was superior to zoledronic acid in delaying the time to first on-study SRE (HR = 0.83; p value less than 0.001), with a median delay of more than eight months in the time to first on-study SRE for patients who received denosumab versus those who received zoledronic acid. Furthermore, denosumab was also superior to zoledronic acid in delaying the time to first and subsequent SREs (HR = 0.82; p value less than 0.001).
Safety data from the three denosumab clinical trials demonstrated a decrease in acute phase reactions and less renal toxicity in patients treated with denosumab. Hypocalcemia occurs more frequently with denosumab -- especially in patients who did not take the recommended daily supplements of calcium and vitamin D.
Osteonecrosis of the jaw (ONJ), which was monitored and adjudicated in the three Phase III denosumab trials, was found to occur infrequently, with a similar incidence in the treatment groups -- 1.4 percent in the patients receiving zoledronic acid and 1.8 percent in those receiving denosumab.
In practice, my approach is to treat all solid tumor patients with bone metastases with denosumab, and all myeloma patients with bone involvement with zoledronic acid.
In summary, malignant bone lesions from solid tumors or multiple myeloma are associated with significant morbidity, decrease in quality of life, and survival. Over the past two decades zoledronic acid has allowed us to successfully treat hypercalcemia. The incidence of skeletal-related events has been decreased by approximately two-thirds by the use of zoledronic and subsequently denosumab. However, since neither bone-targeted agent has demonstrated an effect on progression-free or overall survival, there is still much that needs to be accomplished in our treatment of these patients.