Adyanmic bone disease (ABD) is a bone condition that is characterized by absent or very low bone turnover, which can lead to bone fragility and increased risk for fracture. The focus of this dissertation was to develop a mouse model of ABD that directly targeted osteoblasts and osteoclasts to generate the cellular hallmark of this disease. This mouse model was then used to investigate the independent and interactive effects of age and ABD on bone quality, and possible mechanisms of age-related decline in bone formation.

The Col2.3∆tk (DTK) transgenic mouse was used for all aims in this study. The DTK mouse expresses a truncated version of the HSV-tk gene (∆tk) driven under a 2.3kb fragment of the rat type I collagen α1 (Col1a1) promoter, in which concomitant treatment with ganciclovir (GCV) and pamidronate induces a loss of bone turnover. GCV depletes differentiated osteoblasts to prevent bone formation while pamidronate inhibits bone resorption by osteoclasts.

This mouse model of ABD showed a profound suppression in bone formation and resorption, and it has the histological hallmarks of the human condition. Aged ABD mice revealed that bisphosphonate treatment had a protective effect on trabecular bone volume and microarchitecture. However, it did not protect against age-related deterioration of bone mechanical properties and this deterioration may be due to changes beyond the mineral phase. Lastly, GCV-induced osteoblast depletion caused bone marrow stress that aged the DTK mouse skeleton by decreasing the number and osteogenic potential of progenitor cells.

Our findings suggest that bone mineral density testing and even trabecular structure may not be sufficient indices for bone health in ABD. Understanding how bone cells age and their involvement in bone homeostasis may provide novel targets and paradigms for the intervention of age-related bone loss.