**2.6 Targeted radionuclide therapy**

Systemic therapy with appropriate radionuclide has been accepted as a common treatment modality for patients with various bone metastases [29]. In this treatment, radionuclides are combined with targeted agents with the aim of specific uptake into bone tissue. Radiopharmaceuticals have several advantages over local radiotherapy over topical radiation therapy: they can be administered intravenously, they can target very small metastases (micro-metastases), they can treat several separate affected areas at the same time, and they have fewer side effects, including they cause nausea, vomiting, diarrhea, and tissue damage [30]. However, in this type of treatment, the bone marrow as a critical organ receives a dose, and the absorbed dose of the bone marrow needs to be considered as a limiting factor in treatment [31, 32].

Beta-emitters were found to have a response rate of 70% in a systematic review that included 57 studies. Not only does radionuclide-targeted therapy alleviate pain, but it reduces or defers the incidence of skeletal-related events (SRE). Ionizing radiation is delivered to areas with increased osteoblast activity using these agents, which substitute calcium or bind to hydroxyapatite in bones. Radiation should be targeted at metastatic foci while sparing non-affected tissues to the maximum extent possible. In order to achieve the best results, many radiopharmaceuticals have been studied.

Physicians choose appropriate radiopharmaceuticals based on a number of factors, such as metastatic disease extent, renal function, bone marrow reserve, and availability.

### **2.7 Radionuclides used to relieve bone metastases**

Common radionuclides for the treatment and relief of pain from diffuse bone metastases include Phosphorus-32, Strontium-89, Samarium-153, Rhenium-186,

Rhenium-188, Lutetium-177, and Radium-233. The first radionuclide used for this purpose was Phosphorus-32, which is currently rarely used due to the high energy and consequent high range of emitted beta-particles and the unacceptable absorbed dose in the bone marrow. Rhenium-186 has been approved in Europe, while Rhenium-188 and Luteinium-177 are still being studied as promising radionuclides [33, 34]. Currently, Cerium-141 is being studied as a new promising beta-emitter radionuclide [35, 36].

Radium-223 has also recently been approved by the Food and Drug Administration (FDA) as an alpha radionuclide for those patients with bone metastases without visceral metastases [37, 38]. Patients treated with Ra-223 survived 3.6 months longer and experienced reduced skeletal morbidity compared with those treated with a bisphosphonate. There were no significant side effects associated with Ra-223, which improved QOL. Ra-223 is now being investigated in both endocrine and cytotoxic combinations, after it was approved for use in late-stage disease [39, 40]. Today, Samarium-153 and Strontium-89 are the most widely used radionuclides for bone metastases that are approved by the Food and Drug Administration and have decades of clinical use [41, 42].

Radionuclides are routinely administered in clinical practice as monotherapies. However, radionuclides have been studied in conjunction with other therapies, specifically for prostate cancer. An early study reported an 11-month increase in survival rates if Strontium-89 was added to chemotherapy with doxorubicin [43]. A follow-up study combined beta-emitting bone agents with chemotherapy made in response to this encouraging result. Cancer patients who are castrate-resistant to chemotherapy may benefit from docetaxel because it relieves their pain and improves their quality of life [44]. Strontium-89 combined with docetaxel was found to be a safe combination for concomitant administration in a phase I study [45]. According to Fizazi et al. [46], Sm-153-EDTMP was studied in combination with docetaxel in a single-arm phase II trial. Comparing this study with reference data, the authors reported that the treatment was well tolerated and resulted in an improved overall survival rate. Monoclonal antibodies are used to treat osteoclastic diseases including denusomab. The combination of denusomab with Ra-223 was found to be more effective than Ra-223 alone in reducing symptoms of skeletal events [47].

#### **2.8 New targeted agents for palliative therapy of bone metastases**

A number of new targeted agents are being developed as we gain a deeper understanding of the signaling mechanisms between bone cells and tumor cells. The agents include cathepsin K inhibitors (an osteoclast-derived enzyme that is involved in bone resorption), an antibody against PTHrP, Src kinase inhibitors (a key molecule in osteoclastogenesis), and various anabolic agents. As time goes on, it will be possible to learn how these agents can be used to prevent and treat bone metastases.
