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Distraction osteogenesis is a widely used surgical technique to treat bone deformity and shortening. Several biological treatments have been studied to enhance bone formation during distraction osteogenesis in animals. However, role of osteoactivin in the osseous tissues during distraction osteogenesis remains poorly understood. In this animal experimental study, we investigated the spatiotemporal expression of osteoactivin by immunohistochemistry and real-time PCR using a mouse model for tibial lengthening. Furthermore, to address the role of osteoactivin in bone lengthening, we subjected the osteoactivin-transgenic mice to distraction osteogenesis model. During the lag phase, the fibroblast-like cells (possible progenitors of the osteoblasts or chondrocytes), which mainly express osteoactivin, were infiltrated into the osteotomy site. Osteoactivin was ubiquitously expressed in the lengthened segment during the distraction and consolidation phases. Consistent with the immunohistochemical analysis, the levels of the osteoactivin transcripts in the tibias were significantly increased throughout the distraction osteogenesis process. The bone mineral content in the osteoactivin-transgenic mice calculated using peripheral quantitative computed tomography was also significantly increased at the remodeling zone. The histomorphometric analysis revealed that newly formed callus resorption in the remodeling zone was significantly reduced but bone formation was not altered in the osteoactivin-transgenic mice. We conclude that osteoactivin functions as an inhibitor of callus resorption during the consolidation phase of distraction osteogenesis., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Despite the general clinical acceptance of distraction osteogenesis and much attention to bone formation in this method, little is recognized about activated bone resorption in the regenerated bone. The purpose of this study was to demonstrate the simultaneously activated bone resorption with activated bone formation and to investigate the role and efficacy of bisphosphonate in distraction osteogenesis. Left tibiae of 54 immature rabbits were lengthened for 3 weeks at a rate of 0.7 mm/day after a 1-week lag. Regenerated bone was quantitatively investigated by radiographic bone density, bone histomorphometry, and three-point bending testing. Animals received either vehicle or nitrogen-containing bisphosphonate (N-BP), YM529/ONO5920 at doses of 0.4 mg/kg/w or 0.004 mg/kg/w for 6 weeks. Regenerated bone of the vehicle group showed a radiologically characteristic zone structure containing the osteopenic zones adjacent to the sclerotic zones. The regenerated bone of the 0.4-mg/kg/w group showed no osteopenic zones during the course and eventually became homogeneously radiodense. The bone volume corresponding to the osteopenic zone of this group was 5.6-fold greater compared with that of the vehicle group. The lengthened bone strength of this group was 3.3-fold greater in ultimate force than that of the vehicle group and equivalent to the contralateral tibia. The 0.004-mg/kg/w group had no substantial differences compared with the vehicle group, despite radiological enhancement of the mineralized front as well as somewhat delayed bone resorption. These results demonstrate that not only bone formation but also bone resorption is highly activated in the regenerated bone, implying high bone turnover. Sufficient N-BP caused a notable modulation in morphological properties of the regenerated bone through inhibition of highly activated bone resorption and eventually increased mechanical properties.

Abstract: Several methods have been used to increase bone mass in distraction osteogenesis. Since bone resorption as well as regeneration is stimulated in the distracted segment, bisphosphonate can be a beneficial agent for distraction osteogenesis. Here, we examined the effects of bisphosphonate injected continuously into the regenerate on bone volume, and architectural and mechanical properties of distraction osteogenesis. The left tibia of Japanese White rabbits (n =66) was subjected to slow distraction using an external fixator. At the beginning of the consolidation phase, alendronate (7 μg/kg/day) was infused directly into the lengthened segment for 14 days using an osmotic pump. Control rabbits were infused with phosphate buffered saline (PBS). The tibiae were monitored weekly by soft X-ray and dual-energy X-ray absorptiometry (DXA). The animals were sacrificed at 4, 6, and 8 weeks after operation to examine bone mineral density (BMD) and cortical bone thickness (CBT) by peripheral quantitative computerized tomography (pQCT), while the mechanical property of the lengthened tibia was measured by three-point bending test. In PBS-infused control animals, bone mineral content around the lengthened segment began to decrease after the first week of consolidation phase, forming a tubular bone structure with thin cortex. Infusion of alendronate increased peak bone mineral content around the lengthened segment. At the end of the experiment, volumetric BMD, CBT and mechanical strength of the lengthened segment of the treatment group were approximately twice those of the control animals. Alendronate infused in this manner significantly prevented the osteopenia that critically began early in the consolidation phase, though the dose used in this study was relatively low and no adverse events were noted. [Copyright &y& Elsevier]