*3.1.1 Bisphosphonates*

Bisphosphonates are medications that act as analogs of pyrophosphate, which is a natural inhibitor of bone metabolism. The mechanism of their action has not yet been fully elucidated, but they are inhibitors of osteoclast activity and inductors of their apoptosis, reducing the process of bone remodeling. Bisphosphonates are incorporated into the hydroxyapatite bone matrix, at the site of the OH group of bisphosphonates, using the P-C-P compound, which alters bone microstructure by slowing bone growth and reducing the amount of mineral dissolution in bone. Unlike osteoclasts, osteoblastic activity does not decrease, but remains preserved, which results in an increase in bone mass. There are currently three generations of bisphosphonates on the market. The first generation of nitrogen-free bisphosphonates has the least potential for jaw osteonecrosis. The main side effect of bisphosphonate therapy is osteonecrosis of the jaw [2]. Other side effects that may occur in bisphosphonate therapy are: gastrointestinal disorders (nausea and vomiting), atypical femoral fractures, esophageal inflammation with consequent mucosal erosions, secondary hyperparathyroidism, atrial fibrillation, eye outbursts, muscle pain and others [14–17]. Bisphosphonates are excreted by the kidneys, after accumulation at sites of active remodeling (both jaws). Their characteristic is also rapid deposition in the bones and their long retention in the same (the half-life of zoledronic acid is 11.2 years in the bones) [18]. There are two types of bisphosphonate administration, oral and intravenously.

**Oral bisphosphonates** are medications that are most commonly prescribed in the treatment of osteoporosis and osteopenia, also they are the medications of choice for bone diseases that occur less frequently, such as Paget's disease, osteogenesis imperfecta, chronic recurrent multifocal osteomyelitis and for prevention heterotopic ossifications mostly of the spinal cord [19, 20]. They are also indicated in treatment of chronic kidney disease, kidney transplantation, in rheumatoid diseases related with systemic bone loss such as rheumatoid arthritis, spondylarthritis or SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome and in non-inflammatory rheumatoid diseases, as aseptic osteonecrosis, neuropathic osteoarthropenia, and fibrous dysplasia [21]. Unlike intravenous bisphosphonates, have a lower potential for osteonecrosis.

**Intravenous bisphosphonates** are the most potent in causing osteonecrosis [22]. They are used in the treatment of various conditions associated with malignant diseases such as hypercalcemia caused by cancer and for treatment of bone metastases (secondaryism) [23]. Secondaryism in bones are releasing cytokines and growth factors, which enhance the effectiveness of osteoclasts and consequently bone resorption, which favors tumor growth. Intravenous bisphosphonates stimulate antitumor immune mechanisms, which inhibit growth, migration, and secondary formation, most commonly in breast and prostate cancer. This type of bisphosphonates is very common used in treatment of lytic lesion and for prevention of massive bone resorption in multiple myeloma. Patients with this diagnosis are often treated with aggressive chemotherapy which one of many side-effects is osteonecrosis. Despite the mentioned facts, these medications have positive effect on patient's quality of life [24].

### *3.1.2 Denosumab*

Denosumab are humanized monoclonal antibodies directed to a RANK ligand (modeling regulator) that inhibit osteoclasts and reduce bone resorption [25]. It is used for treatment of osteoporosis in which there is an increased risk of bone fractures, in osteoporosis where there is bone loss due to the use of various drugs and in the treatment of malignant bone lesions diseases. Denosumab therapy is a better option than bisphosphonate therapy, especially with renal dysfunction. The potency of denosumabs to induce osteonecrosis alone has been shown to be approximately similar to the potency of zoledronic acid which is the most potent bisphosphonate [26, 27].

Denosumabs are administered subcutaneously and, unlike bisphosphonates, do not accumulate in bone, so that their effect on bone remodeling is reversible and lasts approximately six months [28].

### **3.2 Antiangiogenic drugs**

Antiangiogenic medications prevent the formation of new blood vessels binding to various signaling molecules that inhibit angiogenesis.

#### *3.2.1 Bevacizumab*

Bevacizumab is humanized monoclonal antibody that binds selectively to a protein called vascular endothelial growth factor (VEGF) in the blood and lymph vessels. It is used in the treatment of malignant diseases of the kidneys, gastrointestinal tract, lungs and glioblastoma [9, 10].

#### *3.2.2 Sunitinib*

Sunitinib is used in the treatment of gastrointestinal tumors, metastatic renal cell carcinomas cells and neuroendocrine tumors of the pancreas. It works by inhibiting thyroxine kinase function. In combination with chemotherapy or bisphosphonates, they have high risk of inducing osteonecrosis [29].
