**1. Introduction**

Osteonecrosis as term represents the death of bone tissue in the body and causes of necrosis can be different. If it is associated with a reduced or complete absence of blood supply, this process is called avascular necrosis of the bone and is most commonly associated in the literature with the femur bone [1].

Radiotherapy (radiation) can also adversely affect bone tissue due to compromised angiogenesis resulting in avascular necrosis with hypoxic, hypocellular, and hypovascular lesions, termed osteoradionecrosis [1]. In 2003, when 36 cancer patients receiving treatment with pamidronate or zoledronate developed a painful bone exposure of the mandible, of the maxilla or both, which was unresponsive to medical and surgical treatment, a new type of osteonecrosis of the jawbone associated with bisphosphonate was called osteonecrosis of the jaw (BRONJ) [2].

Over time, precisely in 2010, new drugs have been identified, such as denosumab for causing osteonecrosis, that do not belong to the group of bisphosphonates so the name has changed to medication-related osteonecrosis of the jaw (MRONJ) [3]. MRONJ is an uncommon condition that can occur after exposure to medication to prevent bone complications, such as bisphosphonates or denosumab or other agents as angiogenesis inhibitors [4]. In most cases it manifests as exposed bone in the maxillofacial region, although non-exposed MRONJ has also been recognized [5–8].

The purpose of this chapter was to describe medication-related osteonecrosis of the jaw, the theory of its development, clinical picture, classification, epidemiology and modalities of treatment, including biostimulative and antimicrobial photodynamic therapy, of medication-related osteonecrosis of the jaw.

### **2. The process of bone remodeling**

Bone remodeling is a physiological process that lasts lifetime and is characterized by the interaction of bone-forming cells - osteoblasts and bone-resorbing cells - osteoclasts. The remodeling process begins with the activation of osteoclasts (multinuclear cells of the monocyte–macrophage system) which are located on the bone surface and with the formation of acidic medium, they dissolve mineralized bone with the breakdown of proteins of the remaining bone matrix. This resorption process takes between two and four weeks. After the resorption process, osteoblasts replace osteoclasts (cells of mesenchymal origin) which synthesize osteoid and organic matrix over a period of two to four months, as a prerequisite for bone mineralization or calcium hydroxyapatite mineral investment [2]. Finally, when osteoblasts are implanted in the bone matrix, they become osteocytes [3]. The presence of osteocytes is extremely important for bone vitality because they can recognize and respond to a variety of mechanical stimuli by regulating the differentiation of osteoblasts and osteoclasts. The remodeling process is regulated by various mechanisms, of which the most important is the RANK/RANKL/Osteoprotergin system. Osteoblasts secrete osteoprotergin, which prevents osteoclast differentiation from precursor cells and thus inhibits resorption. On the other hand, RANKL (Receptor Activator of NF-kb Ligand) along with M-CSF (Macrophage Colony-Stimulating Factor) stimulates osteoclast differentiation and maturation from precursor cells [4]. If this physiological process is disturbed, and this is especially important with increased expression of RANKL, resorption occurs. RANKL is produced by osteoblasts and activated T lymphocytes.

During remodeling and healing of bone fractures, osteoblasts activate various bone morphogenetic proteins that stimulate the production of VEGF (Vascular Endothelial Growth Factor) factor, which is necessary for the formation of new blood vessels, or angiogenesis [5].

The process of physiological remodeling can be disrupted in a variety of diseases and conditions associated with hyperactivated osteoclasts that have a high potential for bone destruction, which can result in hypercalcemia, decreased bone density, and consequent spontaneous fractures. The most common metabolic disease of the skeletal system is osteoporosis which is characterized by osteoclast hyperactivity with loss of bone quality. Malignant diseases of the breast, prostate, lungs, kidneys and thyroid often metastasize to bone. Complications of bone metastases include bone pain, fractures, hypercalcemia, and cachexia. Once formed in the bones, malignant cells stimulate bone resorption where various growth factors, released during bone destruction from the bone matrix, serve them for further growth and proliferation. In addition to growth factors, VEGF factor is also important for later tumor growth. Multiple myeloma, a malignant hematological disease, which is

manifested by the presence of lytic lesions in the bone, has a similar mechanism of bone destruction. In the treatment of these diseases, antiresorptive drugs that directly or indirectly inhibit osteoclasts and antiangiogenic drugs that inhibit VEGF are used.
