Alendronate and PTH Differentially Modulate Bone Quality and Reduce Adiposity in an OVX Rat Model

Abstract

Post-menopausal osteoporosis is defined by a reduction in bone quantity and quality. Bone quality is an accumulation of factors including bone mass, structure, geometry, microarchitecture, tissue mineral density and chemistry. Currently, osteoporosis is treated with pharmaceuticals such as anti-catabolic bisphosphonates such as alendronate (ALN) which maintains bone mass by blocking bone resorption, or anabolic drugs such as parathyroid hormone (PTH) which increases bone mass by increasing bone formation. Due to their different modes of preserving bone, there may be differential drug-driven alterations to bone tissue quality which affect bone strength. Additionally, osteoporosis is associated with increased body mass and abdominal adiposity, factors that pose secondary risk to skeletal health; however, the effects of osteoporosis drugs on adiposity are unclear. The overall objective of this dissertation was 1.) to determine drug, dosage and duration-specific changes to bone composition and its relationship to bone mechanical properties, 2.) to determine drug-induced tissue age specific changes in bone chemistry and its relationship to micromechanical properties and 3.) to determine the interrelationship between bone quality and adiposity during drug treatment. Bone mass, morphology and microarchitecture were reduced after ovariectomy but dose-dependently improved with PTH and ALN. However, high dose ALN and PTH reduced tissue mineral density and tissue level mechanical properties. A finite element model revealed architecture and structural properties accounted for 91% of the change in bone stiffness, where chemistry and tissue properties did not influence bone strength. ALN and PTH had differential effects on bone metabolism which led to alterations in bone chemistry and the micro-mechanical properties of new bone surfaces. ALN had more mineralized, stiffer bone surfaces than PTH. Tissue mineralization positively correlated to changes in micro-mechanical properties. Finally, PTH and ALN significantly improved fat metabolism and altered the relationship between adiposity and bone quality. There was a strong negative relationship between trabecular architecture and marrow adiposity, where drugs altered this interaction through increases of bone coupled with decreases in fat. Overall, bone morphology and architecture are critical components of bone strength. Although small changes to bone material properties did not modulate total bone stiffness, drug-induced changes to chemistry and micromechanical properties provide insight into drug-related effects on tissue quality. Finally, osteoporosis pharmaceuticals may have secondary benefits through mitigation of fat accumulation and could be useful targets for treating diseases such as diabetic osteoporosis due to their beneficial effects on both bone and fat.