Bone metastases—current status of bone-targeted treatments

Multidisciplinary management of bone metastases

In general, the treatment of bone metastases is aimed at palliating symptoms, with cure only rarely a realistic aim in a few rare malignancies such as lymphoma or germ cell tumors affecting bone. Treatments vary depending on the underlying primary site and biological subtype. External beam radiotherapy, endocrine treatments, chemotherapy, and targeted and immunological therapies are all important. In addition, orthopedic intervention may be necessary for the structural complications of bone destruction or to relieve spinal cord and/or nerve root compression. Complementing these treatments is the role of bone-targeted agents that include bisphosphonates, denosumab, and the bone-targeted radiopharmaceuticals.

Bone-targeted agents in oncology

Bone-targeted agents have been used in cancer patients for nearly 30 years, initially to treat hypercalcemia of malignancy, then for the prevention of skeletal morbidity from bone metastases and more recently in early cancer patients to prevent treatment-induced bone loss and, in some clinical situations, to prevent disease recurrence in bone and improve survival.

The bisphosphonates are the most established type of bone-targeted agents with two molecular subgroups, nonnitrogen-containing and nitrogen-containing compounds, with somewhat different molecular effects on osteoclasts. In oncology, clodronate is the only nonnitrogen-containing bisphosphonate approved for use. The nitrogen-containing bisphosphonates are more potent osteoclast inhibitors and, for oncology use specifically, include pamidronate, ibandronate, and zoledronate. Bisphosphonates decrease bone resorption and increase mineralization by specifically inhibiting osteoclast activity with little direct effect on bone formation. After uptake in the skeleton, primarily at active remodeling sites, bisphosphonates are released into the acidic environment of the resorption lacunae and then taken up by endocytosis by the adjacent osteoclasts. Once within the osteoclast, bisphosphonates induce cellular disruption and ultimately apoptosis of the resorbing osteoclast [ ].

In preclinical models, the nitrogen-containing bisphosphonates have also been shown to influence macrophages, gamma delta T lymphocytes, and osteoblasts. In addition to their effects on host cells, bisphosphonates may also have antitumor and/or antiangiogenic effects, but the clinical relevance of these observations remains controversial. Investigations are ongoing to better define the clinically relevant antitumor effects of bisphosphonates in patients with cancer [ ].

Denosumab is a fully human, monoclonal, synthetic antibody that binds with high affinity to receptor activator of nuclear factor kappa B ligand (RANKL), preventing interaction with its receptor RANK in a way that is similar to the natural endogenous inhibitor, osteoprotegerin (OPG) [ ]. In early clinical development, a single subcutaneous dose of denosumab was shown to cause rapid suppression of bone turnover in multiple myeloma and breast cancer patients [ ] and these findings encouraged the clinical development of this targeted treatment. As a circulating antibody, denosumab probably affects all sites within bone equally whereas the strong affinity of bisphosphonates for hydroxyapatite within active remodeling sites may prevent their even distribution throughout the skeleton, with preferential uptake and sites of increased bone turnover and relatively low uptake at more quiescent sites within the skeleton.

The bone-seeking radiopharmaceuticals, strontium-89 ( ⁸⁹ Sr) and radium-223 ( ²²³ Ra), are calcium mimetics that are preferentially taken up at sites of bone formation where calcium is being incorporated most rapidly into the skeleton. ²²³ Ra is of greater clinical interest as, in addition to preferential targeting of osteoblastic bone metastases, it emits high-energy alpha particles from endosteal surfaces that cause double-strand DNA breaks and highly localized cytotoxic effects within closely adjacent cells (<100 μm penetration within the bone marrow) and thus causes only mild myelosuppression as the majority of the bone marrow is beyond the range of the emitted radiation [ ]. Potent antitumor effects of radium-223 in animal models led to the evaluation of its efficacy and safety in clinical trials in patients with bone metastases from prostate cancer [ ].

Prevention of skeletal morbidity in metastatic bone disease

Although radiotherapy is the treatment of choice for localized bone pain, many patients have widespread pain that is difficult to localize, while others experience recurrence of bone pain after radiotherapy. The bisphosphonates provide an additional treatment approach for the relief of bone pain that is useful across the range of tumor types [ ]. However, it is their success in reducing skeletal morbidity that has led to their introduction into routine treatment of advanced cancer patients with bone metastases. In the last 25 years the bisphosphonates and denosumab have become firmly established as a valuable additional treatment component to minimize skeletal morbidity that is given alongside the evolving and increasingly effective range of current therapies to treat the underlying malignancy ( Table 64.1 ).

Multiple, randomized controlled trials have clearly demonstrated that bisphosphonates and denosumab are effective in reducing skeletal morbidity from metastatic cancer [ ]. Assessments of treatment effects have often used the first-event analyses, such as the proportion of patients with at least one skeletal-related event (SRE) or the time to the first skeletal event. These are objective, albeit conservative, endpoints as they do not take into account all subsequent events. Thus, from a clinical perspective, an aggregate score of symptomatic SREs is more relevant. Multiple-event analyses have been increasingly used, as they are able to model all events and the time between events, allowing the calculation of a hazard ratio that indicates the relative risk of events between two different treatments [ ].