**6. Treatment**

Treatment goals may consist of controlling pain and other symptoms, preserving and restoring function, minimizing the risk of SREs, stabilizing the skeleton, and enhancing local tumor control. Therapeutic options include pain management/analgesia, osteoclast inhibitors, systemic anticancer therapy, radiation therapy, bone-targeting radiopharmaceutical therapy, surgery, and/or image-guided thermal ablation. The choice of treatment is influenced by factors like symptoms, impact on quality of life, performance status, estimated life expectancy, goals of treatment, and preferences of care. Optimal treatment may be complex and may require multimodality treatment strategies.

### **6.1 Analgesia**

Patients with bone metastases will suffer from significant bone pain at some point of the disease course. Initially, for mild to moderate pain, nonopioid analgesic drugs, such as acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), may be used alone, but for moderate to severe pain, opioids should be the therapy of choice, according to the WHO "analgesic ladder" approach [19, 20].

Glucocorticoids may be helpful for selected patients as well as other adjuncts, like antidepressants and antiepileptics such as gabapentin [21, 22]. Actually, for patients with neurologic deficits or pain associated with spinal cord compression, high-dose glucocorticoid therapy is part of the standard treatment - a typical dose is 10 mg dexamethasone intravenously followed by 16 mg daily orally in divided doses, until definite treatment [23].

Multidisciplinary management with a palliative care specialist should be considered for patients whose pain is refractory to analgesia or who develop significant side effects.

## **6.2 Osteoclast inhibitors**

For patients with metastatic bone disease, osteoclast inhibitors, like bisphosphonates and denosumab, may prevent SREs as they slow down or reverse the progression of skeletal metastases and may even improve pain and quality of life. For patients in whom SREs are unlikely (those with minimal bone tumor burden) or those with a limited expected survival, treatment with osteoclast inhibitors should be decided case by case.

**Bisphosphonates** are analogs of pyrophosphate, a natural inhibitor of bone demineralization. Bisphosphonates bind avidly to exposed bone mineral around resorbing osteoclast, and this leads to very high local concentrations of products in the resorption lacunae. Then, they are internalized by the osteoclast, causing disruption of the chemical process involved in bone resorption [2, 7, 8]. This way, bisphosphonates decrease bone resorption and increase mineralization [5].

There are two classes of bisphosphonates: nonnitrogen containing, such as etidronate, clodronate, and tiludronate, and nitrogen containing, such as pamidronate, alendronate, ibandronate, risedronate, and zoledronic acid, which are more potent osteoclast inhibitors [19]. When a bisphosphonate is chosen, zoledronic acid is suggested over other bisphosphonates.

**Zoledronic acid** is the most potent bisphosphonate available and has been the bisphosphonate of choice in most clinical settings and healthcare systems [7]. Trials showed zoledronic acid has effectively decreased the risk of SREs in women with bone metastases from breast cancer, men with bone metastases from castration-resistant prostate cancer, and patients with bone metastases from other solid tumors [24–29]. The approved dose and schedule of administration is 4 mg every 4 weeks, with the dose adjusted for creatinine clearance.

If zoledronic acid is not available, **pamidronate** is a reasonable alternative [25, 29]. Other bisphosphonates that have demonstrated efficacy in reducing SREs were **ibandronate** and **clodronate** [30, 31]. The dosage and interval of administration are described in **Table 2**.

In terms of tolerance, nephrotoxicity is one of the most important side effects, which is both dose and infusion time dependent [5, 32]. Other common adverse effects include acute-phase reactions (with pyrexia and flu-like symptoms), gastrointestinal effects, and the most concerning, osteonecrosis of the jaw [5, 33].

**Denosumab** is a monoclonal antibody that inhibits the RANKL, a key component in the pathway for osteoclast formation and activation [5, 8]. By binding to RANKL, denosumab prevents osteoclast formation, leading to decreased bone resorption and increased bone mass, thus preventing SREs [19]. Several phase III trials have shown a superiority of denosumab when compared to zoledronic acid [34–36]. A combined analysis of these three phase III trials concluded that denosumab was superior to


### **Table 2.** *Dosing and interval of bisphosphonates.*

*Perspective Chapter: Bone Metastases of Solid Tumors DOI: http://dx.doi.org/10.5772/intechopen.108607*

zoledronic acid in reducing the risk of a first SRE (hazard ratio [HR] 0.83, 95% CI 0.76–0.90) and in delaying the time to a first SRE (median 26.6 versus 19.4 months), with no difference in survival outcomes [37]. The recommended dose and schedule of administration is 120 mg every 4 weeks. Most common adverse events are similar to those of zoledronic acid, with the benefit of not requiring monitorization of renal function or dose adjustments for patients with renal insufficiency [37].

### **6.3 Systemic anticancer therapy**

Chemotherapy, targeted therapies, and hormone therapy may contribute to pain relief by reducing tumor bulk and/or by modulating pain signaling pathways [38]. In selecting systemic anticancer treatment for metastatic bone disease, the pathological type of the tumor is the most important [2].

### **6.4 Radiation therapy**

Radiation therapy is commonly used in the management of bone metastases, both for pain relief and for the prevention of morbidity and disease progression [5].

**External beam radiation therapy** (EBRT) is a standard approach for symptomatic skeletal metastases, as it can provide significant palliation of painful bone metastases in 50–80% of patients, with up to one-third of patients achieving complete pain relief at the treated site [39]. For uncomplicated bone metastases, a single fraction of 8 Gy to the involved area has been shown to provide equivalent pain palliation and may be more cost-effective and convenient compared with fractionated regimens, although retreatment is needed more frequently [13, 40].

**Stereotactic body radiation therapy** (SBRT) utilizes precisely targeted radiation to a tumor while minimizing radiation to adjacent normal tissue, allowing the treatment of small or moderate-sized tumors in either a single or a limited number of dose fractions. This approach should be reserved mostly for patients who have a reasonable life expectancy (superior to 6 months) and persistent or recurrent bone pain after a standard course of EBRT, which requires reirradiation [40]. Additionally, SBRT may be preferred over EBRT in the definitive treatment of patients with symptomatic bone metastases from relatively radioresistant neoplasms (such as renal cell cancer, melanoma, and sarcoma), especially in the setting of vertebral metastases with epidural extension and in patients with oligometastatic disease who have a relatively long life expectancy [41, 42].

### **6.5 Bone-targeting radiopharmaceutical therapy**

Bone-targeted radiopharmaceuticals are radioactive bone-seeking molecules that show efficacy for pain control in patients with osteoblastic bone metastases, such as samarium-153, strontium-89, rhenium-186, and radium-223 [5].

**Radium-223** is approved for the treatment of male patients with castrationresistant prostate cancer, with symptomatic bone metastases and no known visceral metastases, as it shows benefit in overall survival (median 14.9 versus 11.3 months, HR 0.70, 95% CI 0.58–0.83) and time to first symptomatic SRE (median 15.6 versus 9.8 months, HR 0.66, 95% CI 0.52–0.83) on a phase III trial, compared to placebo [43]. Its combination with systemic anticancer therapy is being studied; however, the benefit of the combination has not yet been established.
