Healing of fractures in osteoporotic bones in mice treated with bisphosphonates - A transcriptome analysis.

Abstract

Bisphosphonates (BP) are inhibitors of bone resorption and are used to treat postmenopausal osteoporosis. Long-term treatment with BP attenuates bone remodeling, possibly leading to detrimental consequences for the bones' ability to repair defects. To test this hypothesis, an animal model was established. Twelve week old mice were ovariectomized (OVX). Following confirmation of bone loss 8 weeks after OVX, the animals were treated with Alendronate (ALN) until sacrifice. After 5 weeks of ALN injections, the femoral bones were osteotomized and the osteotomies were either rigidly or non-rigidly stabilized. In rigidly fixed defects, no callus developed between 1 and 5 weeks after osteotomy, whereas after non-rigid fixation, callus development occurred. The administration of ALN resulted in an increase in newly formed bone at the defect site 5 weeks after osteotomy, irrespective of the estrogen status or fixation system. Transcriptome analysis demonstrated that both rigid and non-rigid fixation affected gene expression primarily during the middle phase of bone repair. Furthermore, the number of differentially expressed genes in tissues from non-rigidly fixed defect sites increased in animals treated with ALN over the course of bone repair. This indicates that ALN-dependent repair processes become increasingly dominant in the late phases of the healing process. Ranking of the factors affecting the composition of the transcriptome and their impact on the healing process revealed fixation at the defect site to be the strongest causative factor, followed by bisphosphonate treatment and estrogen deficiency. The present study suggests that the continuous administration of ALN is detrimental to bone repair, eventually causing a delay in healing in mechanically compromised situations. Consequently, rigid fixation may prove essential for a successful intervention.