Effects of aging and remodeling on bone microdamage formation

Abstract

Skeletal fragility is characterized by low bone mass, negative changes in bone microarchitecture, and compromised tissue matrix properties, including accumulation of microdamage. Microdamage accumulates in vivo from daily physiological loading and is targeted for repair through a normal remodeling process, thus preventing microcrack growth and potential fracture. However, impaired remodeling is associated with aging and osteoporosis, resulting in an increased accumulation of microdamage which contributes to reduced bone mechanical properties. The current clinical method for assessing increased risk of fracture involves measuring bone mineral density (BMD) of the hip and spine, locations of trabecular bone where high rates of remodeling occur. The bisphosphonate alendronate (ALN) reduces clinical risk for fracture by significantly increasing BMD, but studies have shown a concomitant reduction in intrinsic properties that may be the underlying cause for recent reports of spontaneous fractures with long-term alendronate use. Another anti-resorptive agent called raloxifene (RAL) is a selective estrogen receptor modulator (SERM) and has been shown to modestly improve BMD while decreasing fracture risk to a similar degree as alendronate. The combination of RAL and ALN as a treatment for osteoporosis may provide the benefits of each drug without the negative effects of ALN. Therefore, the overall goal of this thesis was to address the effects of aging and anti-resorptive agents on the properties of bone through the formation of microdamage. Assessment of age-related effects on bone was conducted through quantification of microdamage progression. It was found that old bone results in greater incidences of microdamage progression, reflecting a compromised tissue matrix with reduced resistance to crack growth. Effects of combination treatment with RAL and ALN were evaluated through biomechanical testing, micro-CT imaging, and microdamage quantification. Results showed improved trabecular bone volume and ultimate load with positive effects on trabecular architecture. Combination treatment reduced the proportion of microdamage that may lead to catastrophic fracture, indicating an improvement in the local tissue matrix properties.