Clinical treatments for osteoporosis, such as Hormone therapy (HT) and bisphosphonate drug treatments serve to reduce fracture susceptibility to a certain extent. However, drugs only reduce fracture susceptibility by 50%. This may be owing to the fact that the mechanisms initiating the disease are poorly understood. Although osteoporosis reduces overall bone mass causing bone fragility, recent studies from Prof. McNamara’s group have shown that bone tissue composition is also altered at the microscopic level, and that these changes are undetectable by conventional diagnostic techniques (DEXA), but may contribute to bone fracture. In particular we have shown that bone loss and tissue mineral changes during oestrogen deficiency do not occur ubiquitously, but are more prevalent at specific anatomical regions within the femora of rat and ovine models of osteoporosis. Recent studies in Prof. McNamara’s group have found for the first time that these complex tissue levels changes in bone composition might be explained by alterations in bone cell biology, in particular the mechanobiological responses. Most interestingly we have recently shown that the mechanical environment of bone cells is altered during early-stage osteoporosis. This suggests that a mechanobiological response may have occurred to alter the mechanical environment, perhaps in an attempt to restore homeostasis.