During action of bisphosphonates on bone cells decreases the

During BIS treatment, loss ofbone mineral content is prevented, by inhibiting osteoclastic activity and boneresorption. Due to their high potency and fast acting mechanisms,bisphosphonates may cause potentially serious long-term side effects. Theseside effects include the ONJ, oesophageal cancer and atypical fractures (82).

Case reports had beenconducted to examine the risk factors for ONJ and came to the conclusion thatamong others the long-term treatment of BIS in combination with invasive dentalprocedures, such as implantation and extraction, tobacco and alcohol abuse anda pre-existing periodontal disease are risk factors. Furthermore most of thecases showed signs of infection and appeared to be symptomatic including bonepain, swelling, loosening of teeth and purulent discharge (83, 84). The necrosis of the bonecould be attributable to several mechanisms.

On the one hand the direct actionof bisphosphonates on bone cells decreases the rate of turnover within thebone. A reduction in osteoclastic activity is followed by a decrease of boneforming osteoblast activity, which may lead to a zone of necrosis. On the otherhand the marked reduction of angiogenesis and reduction of endothelial cellsmay decrease the perfusion rate of the bone itself and leads to necrotizing ofthe area. A Hypothesis was also described in which bisphosphonates have asecondary toxic effect on oral mucosal structures and may pave the way for oralpathogens through the damaged oral mucosa and infect the bone. Lastly it wasdocumented that macrophages are also involved by the action of BIS because oftheir similarity to osteoclasts altering their cellular activity and cellnumbers and exposing them for longer periods of time (85).  Additionally long-termantiresorptive therapy may alter the biomechanical properties of the bonematrix due to its effect on mineralization and collagen distribution within thebone, which may result in increased brittleness and stiffness of bone therebymaking it more prone to fracture. BIS also have an antiangiogenic effect, whichmay, in connection with reduced bone remodelling, impair the healing of stressfractures and potentially result in a complete fracture (86).

As the most frequent adverseeffects of oral bisphosphonates, oesophageal and gastrointestinal problems havebeen noted. Several cases confirmed the adverse effects of alendronate and Pamidronatewhere patients developed ulcerative oesophagitis or other oesophagealinflammations (87, 88). However, according tocurrent understanding of the risk of developing oesophageal cancer inconnection with long-term bisphosphonate therapy conflicting results have beenfound. According to a cohort study conducted in the United Kingdom there is noevidence between oesophageal cancer and bisphosphonate therapy (89).  Another BIS hypothesisevaluated the effects of them on the immune regulation. Denosumab affectsmonocyte migration and numbers by blocking RANK-RANKL (previously described inchapter 1) interaction.

Sunitinib negatively influences macrophage-monocytedevelopment by inhibiting M-CSF. Due to the acidic pH of most bone-bound BIS, osteonecrosismay occur more likely (90).