Numerous factors can affect skeletal regeneration, including the extent of bone injury, mechanical loading,
inflammation and exogenous molecules.
Bisphosphonates are anticatabolic agents that have been widely used to treat a variety of
metabolic bone diseases.
Zoledronate (ZA), a
nitrogen-containing
bisphosphonate (N-BP), is the most potent
bisphosphonate among the clinically approved
bisphosphonates. Cases of
bisphosphonate-induced osteonecrosis of the jaw have been reported in patients receiving long term N-BP treatment. Yet,
osteonecrosis does not occur in long bones. The aim of this study was to compare the effects of
zoledronate on long bone and cranial bone regeneration using a previously established model of non-stabilized
tibial fractures and a new model of
mandibular fracture repair. Contrary to
tibial fractures, which heal mainly through endochondral ossification,
mandibular fractures healed via endochondral and intramembranous ossification with a lesser degree of endochondral ossification compared to
tibial fractures. In the tibia, ZA reduced callus and cartilage formation during the early stages of repair. In parallel, we found a delay in cartilage
hypertrophy and a decrease in angiogenesis during the soft callus phase of repair. During later stages of repair, ZA delayed callus, cartilage and bone remodeling. In the mandible, ZA delayed callus, cartilage and bone remodeling in correlation with a decrease in osteoclast number during the soft and hard callus phases of repair. These results reveal a more profound impact of ZA on cartilage and bone remodeling in the mandible compared to the tibia. This may predispose mandible bone to adverse effects of ZA in disease conditions. These results also imply that
therapeutic effects of ZA may need to be optimized using time and dose-specific treatments in cranial versus long bones.