Microdamage: Its Role in the Mechanical Integrity of Low Bone Mass Diseases and its Treatment Implications.

Abstract

Osteogenesis Imperfecta (OI) is a rare low bone mass disease characterized by an increased propensity for fractures. Patients are often young children who are wheelchair bound and severely limited from physical activity. A common treatment is bisphosphonates (BPs), which aim to increase bone mass and strength through reduced bone resorption. Despite some clinical successes in the vertebrae, animal studies have implicated BP’s in the prevention of microdamage repair through the inhibition of osteoclast targeting mechanisms. This study investigated the interplay between microdamage, bisphosphonate treatment, the resulting mechanical integrity, as well as any potential targeting mechanisms that could possibly affect long term repair of microdamage in an OI animal model. This work utilized fluorescent markers, mechanical loading, confocal microscopy, and linear elastic fracture mechanics (LEFM) to answer these questions. Through the use of a mouse model for Type IV OI (Brtl/+) the first portion of this work assessed the susceptibility of OI bone to microdamage accumulation. Significant increases of 217% and 354% in microcrack numerical and surface density in Brtl/+ control limbs versus WT (healthy bone) controlled limbs were observed. Next, we determined the effects of BP treatment on damage accumulation in the growing phase of the mouse. Results suggest that BP treatment may result in a reduction in fatigue life as well as moderate trends in reduction of fracture toughness (Kc) of 12% in Brtl/+ and 21% in WT bone. BP treatment comes with the potential risk that the long term remodeling of microdamage may be compromised. The final portion of this study demonstrated BPs binding to microcracks as well as their surrounding osteocyte lacunae. Additionally, osteocyte apoptosis levels are increased within proximity of microdamage. These results suggest that the long term remodeling of microdamage may be compromised. Currently, BPs are still the most common treatment for patients with OI. The results of this work suggest that BPs may not only potentially inhibit targeted damage repair, but may also have adverse effects on material properties and fatigue life. The results of this study may encourage a more tempered administration of BPs and possibly promote the use of non-binding treatment alternatives.