Abstract
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.
Highlights
Bisphosphonates (BP) are synthetic analogs of pyrophosphate that can be incorporated in vivo into mineralized tissues [1]
Bone volume was significantly higher by day 10 post-fracture and remained high by day 28 in ZA-treated samples compared to controls implying an increase in bone deposition during the soft callus phase of repair followed by a delay in bone remodeling (Fig. 1B, bottom)
Differences between tibial and mandibular fracture repair In this study, we investigated the differences in healing between cranial and long bones and the responses to ZA treatment in these two repair sites
Summary
Bisphosphonates (BP) are synthetic analogs of pyrophosphate that can be incorporated in vivo into mineralized tissues [1] Due to their potent effects on osteoclastic bone resorption, BP are widely used for the treatment and/or prevention of metabolic bone diseases characterized by increased osteoclast activity such as Paget’s disease, metastatic and osteolytic bone diseases, as well as osteoporosis [2]. The first group contains the less potent, non-nitrogen containing BP that can be metabolized into nonhydrolyzable analogues of ATP [4] and the second group contains the more potent, nitrogen containing BP such as alendronate, risedronate, and zoledronate (ZA) These potent BPs interfere with the mevalonate biosynthetic pathway and inhibit protein prenylation, which is important for osteoclast function [2,5]. We assessed the consequences of ZA treatment on cartilage and bone formation within the fracture callus, as well as matrix remodeling, osteoclasts and angiogenesis
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