Table 2.

Most plausible aetipathogenetic paradigms for osteonecrosis of the jaws (ONJ).

Paradigm	Synopsis	Citations
Osteoclast-mediated toxicity	Bisphosphonates suppress osteoclast-mediated bone remodeling. This suppression results in “fatigue” of the alveolar bone, responsible for necrosis	[83–85]
Soft tissue toxicity	The oral mucosa is initially involved. As the damage progresses, underlying alveolar bone is also involved and the clinical presentation of ONJ becomes evident	[79, 86]
Infection	Increased bacterial adhesion to the bisphosphonate covered bone may be the cause for ONJ development	[84, 87]
Impaired immune homeostasis-macrophage impaired function	Dendritic cells, macrophages, cytotoxic and helper T-lymphocytes are affected by bisphosphonates. Chemokines, like tumor necrosis factor-alpha, inteleukins IL-1a, IL-1b, IL-6 and IL-8 are also impaired by bisphosphonates. Impaired immune response is responsible for continued inflammation resulting in osteomyelitis. Impaired function of macrophages due to RANKL inhibition is a key phenomenon in the defective topical immune response	[79, 88–90]