**2.3 Surgery**

Another treatment for bone metastases is surgery. Most people with bone metastases without bone fractures do not need surgery. If a pathological fracture occurs, the first

step in surgery is to fix the fracture site. Preventive surgery is mostly used in metastases with a high probability of fracture in tall bones that support the weight of the body. Vertebroplasty is another method of reducing pain for those patients with vertebral fractures that do not put pressure on the spinal cord but have severe pain [19].

The affected bone should be radiographed and scanned with radionuclides before surgery. Radiotherapy is used to treat every other metastatic lesion that may develop into a pathological fracture after these measures are taken. If methylmethacrylate is used to fix a plate or nail in the bone, a pathological fracture will be more difficult to treat than if there were no implant.

Usually, radiotherapy is the only modality likely to restore mobility and relieve pain in pathological fractures of long bones. For primary internal stabilization of long bones, radiotherapy is the treatment of choice. Even though radiotherapy might control local tumors, it is unlikely that a pathological fracture will heal without treatment. A large area of bone destruction could result in an insufficient matrix for adequate fracture healing, as radiotherapy inhibits chondrogenesis.

#### **2.4 Bisphosphonates**

Another treatment is the use of bisphosphonates. Bisphosphonates prevent bone destruction by causing apoptosis in osteoclast cells and inhibiting the activity of these cells in osteolytic metastases. In patients with bone metastases with increased blood calcium, the use of bisphosphonates with adequate hydration is standard treatment. Bisphosphonates are excreted by the kidneys and should not be used by kidney patients [20, 21]. The bisphosphonate zoledronic acid induces apoptosis of osteoclasts and reduces the risk of skeletal-related events. As a result of large randomized controlled trials, bisphosphonates have become the standard of care for treating and preventing skeletal complications associated with bone metastases in patients with solid tumors or multiple myeloma [22]. In these studies, the primary endpoint was how bone-targeted treatment affected the number of patients experiencing skeletalrelated events (SREs), the rate of SREs, and the time before the first SRE.

Patients with malignant bone diseases can benefit significantly from earlygeneration bisphosphonates, such as sodium clodronate and disodium etidronate. The bisphosphonates are metabolized by osteoclasts into non-hydrolyzable, cytotoxic ATP analogs, which have the effect of directly inducing apoptosis and impair mitochondrial function.

Bisphosphonates containing nitrogen inhibit the enzyme farnesyl diphosphate synthase, in contrast to the early-generation bisphosphonates. As a result, osteoclasts cannot function properly and are less able to resorb bone. There are several nitrogencontaining bisphosphonates, including disodium pamidronate, alendronic acid, ibandronate sodium, risedronate sodium, and zoledronic acid. As a result of their introduction in clinical trials, these agents showed dramatic improvements in therapeutic activity [23, 24].
