Do drugs prescribed to prevent hip fractures in fact cause bones to become weaker?

Abstract

Osteoporosis is the most prevalent metabolic bone disorder worldwide, for which bisphosphonates are the first-line treatment. Bisphosphonates suppress normal bone remodelling and are effective at reducing fracture risk. However, bisphosphonate use is associated with fragility fractures in a small population of patients. This thesis comprises a series of studies designed to investigate the effects of bisphosphonates on the mechanical and structural properties of bone. The first study investigated the effects of bisphosphonate treatment on the microstructural and mechanical properties of bone. Bisphosphonate-treated bone exhibited increased frequency and size of microcracks, which corresponded to reduced tensile strength and stiffness. These findings suggest that the accumulation of microcracks occurring in bisphosphonate-treated bone comprises the microstructure leading to reduced mechanical strength. In the second study, the fracture mechanics of bisphosphonate-treated bone were evaluated. The propagation of cracks in the bisphosphonate group was significantly greater compared with osteoporotic and healthy bone, which highlights a reduction in fracture resistance. There is loss of protective mechanisms against fracture in bisphosphonate-treated bone, thus increasing susceptibility to low-energy fractures. The aim of the third study was to interrogate the effects of bisphosphonate treatment on bone mechanics at the nanoscale. Mineral strain reached a peak at the maximum tissue strain, preceding the onset of fibril sliding. There was initiation of fibril sliding at a higher tissue strain than that corresponding to ultimate tensile strength but at a lower tissue strain than that corresponding to fracture. Hence, the mechanisms contributing to reduced macroscopic strength observed in bisphosphonate-treated bone can be attributed to the effects the mineral’s ability to contribute to the load carrying capacity of the bone. The present findings suggest that there may be a population of patients in whom bisphosphonate therapy does not confer protective effects against fractures but is associated with micro- and nanostructural alternations and increased bone fragility instead.