Locally administered low-dose alendronate increases bone mineral density during distraction osteogenesis in a rabbit model

Abstract

We investigated the effect of locally administered bisphosphonate on distraction osteogenesis in a rabbit model and evaluated its systemic effect. An osteotomy on the right tibia followed by distraction for four weeks was performed on 47 immature rabbits. They were divided into seven equal groups, with each group receiving a different treatment regime. Saline and three types of dosage of alendronate (low, 0.75 microg/kg; mid, 7.5 microg/kg and high 75 microg/kg) were given by systemic injection in four groups, and saline and two dosages (low and mild) were delivered by local injection to the distraction gap in the remaining three groups. The injections were performed five times weekly during the period of distraction. After nine weeks the animals were killed and image analysis and mechanical testing were performed on the distracted right tibiae and the left tibiae which served as a control group. The local low-dose alendronate group showed a mean increase in bone mineral density of 124.3 mg/cm(3) over the local saline group (analysis of variance, p < 0.05) without any adverse effect on the left control tibiae. The findings indicate that the administration of local low-dose alendronate could be an effective pharmacological means of improving bone formation in distraction osteogenesis.

Effect of Risedronate on Bone Resorption during the Consolidation Phase of Distraction Osteogenesis: A Rabbit Model

“…[22][23][24] In an animal model of distraction osteogenesis, a low dose is more effective than a mid dose local use of alendronate in preserving the BMC of the lengthened segments; higher doses of alendronate could lead to inhibition of osteoblasts and therefore affect outcomes adversely. 17 In our study, low-dose continuous local injection of risedronate increased both BMC and BMD of the newly formed bone segments and prevented osteoporosis in the bone regions proximal and distal to the lengthened segments. The BMC of the lengthened segments was 65% higher in the risedronate group, as was in the segments proximal and distal to the regenerate bone (31% and 21%, respectively).…”

“…5 Low-dose injection to the distraction site diminishes the chance of systemic drug dispersion. Recent in vitro and in vivo studies are all in favour of low drug concentrations 17,[22][23][24] ; low-dose N-BPs are capable of inhibiting bone resorption (by osteoclasts) and stimulating osteoblasts, which in turn promotes new bone formation. Conversely, higher doses of N-BPs may result in osteoblast inhibition.…”

“…These findings support the effectiveness of local administration of N-BPs and are in consistent with previous studies with the local use of N-BPs other than risedronate. 17,25 Mechanical properties of the regenerate bone in distraction osteogenesis are of utmost importance for clinical practice. In our study, the ultimate mean load to failure in the lengthened bone of the residronate group was 77±26 N, as compared to 71±10 N in the PBS group (p=0.621).…”

“…16 Local injection of low-dose alendronate during distraction osteogenesis can prevent bone resorption, though it has no beneficial effect on the mechanical properties of the regenerate bone. 17 Moreover, direct infusion of low-dose alendronate into the lengthened segment during distraction osteogenesis prevents the osteopenia that begins early in the consolidation phase. 18 Risedronate is among the most potent bisphosphonates (5 to 10 fold that of alendronate), 19 but it may be associated with a higher rate of jaw osteonecrosis.…”

Alendronate promotes bone formation by inhibiting protein prenylation in osteoblasts in rat tooth replantation model

“…This and earlier (Wilkinson & Little 2011) studies further add a possibility that local application of N-BPs may be useful for local bone augmentation. It has been reported that locally administered ALN increased bone mineral density in a rabbit model (Omi et al 2007). Surface coatings of zoledronate and pamidronate have also been reported to cause bone increase around orthopedic implants in animal models (Tanzer et al 2005, Wermelin et al 2008, Gao et al 2009).…”