Effect of dosing interval duration of intermittent ibandronate treatment on the healing process of femoral osteotomy in a rat fracture model

Abstract

The effects of bisphosphonate treatment schedule on fracture healing have not previously been tested. We evaluated the effect of ibandronate dosing interval duration on healing following surgical "fracture" (osteotomy) using a rat femoral fracture model. Six-week-old rats (n = 160) underwent osteotomy and were then allocated into vehicle control (CNT) or an ibandronate treatment group: 5 μg/kg daily (DAY, 5 days/week), 75 μg/kg once every 3 weeks (I-3), 150 μg/kg once every 6 weeks (I-6), resulting in the same total ibandronate dose over the study. Rats were killed after 6 or 18 weeks. At 18 weeks, all fracture lines had disappeared in the CNT and I-6 groups; approximately 10% of fracture lines remained in the DAY and I-3 groups. Ibandronate-treated groups showed large callus areas around the fractures, which shrank between 6 and 18 weeks after surgery; the extent of shrinkage decreased with shorter dosing interval. In histomorphometry, callus remodeling was suppressed by ibandronate; this became more apparent at shorter dose intervals. The structural properties of osteotomized femora were increased in the DAY group compared with CNT, but intrinsic material properties reduced inversely and became closer to those of CNT in response to increased dosing interval. Ibandronate induced formation of large calluses around osteotomies but delayed woven bone remodeling into lamellar bone and reduced intrinsic material properties in a rat fracture model. Extending the dosing interval of intermittent ibandronate treatment appeared to reduce the suppression of callus remodeling caused by ibandronate, which would have delayed healing after osteotomy.

Fig. 1

Soft X-ray photography of fractured femora. Fracture lines had disappeared in almost 90% of the control group but were still present in more than half of ibandronate-treated groups at 6 weeks postfracture. At 18 weeks all fracture lines had disappeared in control and I-6 groups; however, about 10% of fracture lines remained in the DAY and I-3 groups

Fig. 2

Contact microradiographs of cross-sectional specimens at the fracture plane. At 6 and 18 weeks after osteotomy ibandronate treatment groups had visually larger calluses than CNT. At 18 weeks the callus sizes of all groups appeared to be smaller than at 6 weeks and new cortical shell was apparent, which was still porous in the DAY group

Fig. 3

Photomicrographs of the callus at 6 and 18 weeks after osteotomy, under epifluorescence and polarized light. At 6 weeks The labeled surface and lamellar bone in the callus were less in all treatment groups than CNT. At 18 weeks lamellar bone formation was active in the CNT and I-6 groups, while less lamellar and more woven bone were observed in the DAY group than in any other groups