January 19, 2020

During action of bisphosphonates on bone cells decreases the

During BIS treatment, loss of
bone mineral content is prevented, by inhibiting osteoclastic activity and bone
resorption. Due to their high potency and fast acting mechanisms,
bisphosphonates may cause potentially serious long-term side effects. These
side effects include the ONJ, oesophageal cancer and atypical fractures (82). Case reports had been
conducted to examine the risk factors for ONJ and came to the conclusion that
among others the long-term treatment of BIS in combination with invasive dental
procedures, such as implantation and extraction, tobacco and alcohol abuse and
a pre-existing periodontal disease are risk factors. Furthermore most of the
cases showed signs of infection and appeared to be symptomatic including bone
pain, swelling, loosening of teeth and purulent discharge (83, 84). The necrosis of the bone
could be attributable to several mechanisms. On the one hand the direct action
of bisphosphonates on bone cells decreases the rate of turnover within the
bone. A reduction in osteoclastic activity is followed by a decrease of bone
forming osteoblast activity, which may lead to a zone of necrosis. On the other
hand the marked reduction of angiogenesis and reduction of endothelial cells
may decrease the perfusion rate of the bone itself and leads to necrotizing of
the area. A Hypothesis was also described in which bisphosphonates have a
secondary toxic effect on oral mucosal structures and may pave the way for oral
pathogens through the damaged oral mucosa and infect the bone. Lastly it was
documented that macrophages are also involved by the action of BIS because of
their similarity to osteoclasts altering their cellular activity and cell
numbers and exposing them for longer periods of time (85). 

Additionally long-term
antiresorptive therapy may alter the biomechanical properties of the bone
matrix due to its effect on mineralization and collagen distribution within the
bone, which may result in increased brittleness and stiffness of bone thereby
making it more prone to fracture. BIS also have an antiangiogenic effect, which
may, in connection with reduced bone remodelling, impair the healing of stress
fractures and potentially result in a complete fracture (86).

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As the most frequent adverse
effects of oral bisphosphonates, oesophageal and gastrointestinal problems have
been noted. Several cases confirmed the adverse effects of alendronate and Pamidronate
where patients developed ulcerative oesophagitis or other oesophageal
inflammations (87, 88). However, according to
current understanding of the risk of developing oesophageal cancer in
connection with long-term bisphosphonate therapy conflicting results have been
found. According to a cohort study conducted in the United Kingdom there is no
evidence between oesophageal cancer and bisphosphonate therapy (89).  

Another BIS hypothesis
evaluated the effects of them on the immune regulation. Denosumab affects
monocyte migration and numbers by blocking RANK-RANKL (previously described in
chapter 1) interaction. Sunitinib negatively influences macrophage-monocyte
development by inhibiting M-CSF. Due to the acidic pH of most bone-bound BIS, osteonecrosis
may occur more likely (90).


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