The biological mechanisms of the antiresorptive therapy of osteoporosis, and the antiresorptive drug related osteonecrosis of jaws

Abstract

Osteoporosis (OP) is one of the most common debilitating conditions in the population over the age of 50. Its pathomechanism is still not fully understood. Nowadays, in elderly population, the most common approach to control bone loss is blocking osteoclastic activity by administration of antiresorptive drugs. Such drugs are also used for the management of metastatic bone cancer, hypercalcemia of malignancy, and other conditions with elevated osteoclastic activity. Bisphosphonate therapy is the first choice, but recently monoclonal antibody to RANKL (receptor activator for nuclear factorkappa B ligand), has also been used; each with distinct mechanism of actions. Bisphosphonates irreversibly adhere to bone minerals, and during bone remodelling, osteoclasts internalise and metabolise matrix-bound bisphosphonates. Subsequently, they damage cytoskeletal organization and ruffled border integrity, resulting in the eventual osteoclast apoptosis. On the other hand, denosumab blocks osteoclast neogenesis by neutralizing RANKL, which is necessary for osteoclast precursor differentiation into mature osteoclasts. Thus, bisphosphonates acts on mature osteoclasts, while denosumab hinders osteoclast formation from its precursors. Although their antiresorptive actions are different, recent case reports and controlled clinical studies indicated that administration of either of these may be associated with development of osteonecrosis of the jaw (ONJ). The fact that ONJ is associated with both bisphosphonates and denosumab convincingly suggests that osteoclast suppression is essential in the pathomechanism of ONJ. The evidence-based, cause-related therapy for MRONJ still remains missing. Many alternative therapeutic approaches has recently been tested and published, amongst them, using recombinant human parathyroid hormone (rh-PTH, teriparatide) may become a promising treatment modality

Keywords

• osteoporosis
• antirezorptive therapy
• coupled bone remodelling
• medication related osteonecrosis of jaws