Altered bone microstructure is a major component of osteoporosis and bone fragility. Whilst an important standard by which to diagnose and make treatment decisions for osteoporosis, the evaluation of bone mineral mass by dual-energy X-ray absorptiometry (DXA) at spine or hip is not sufficient for understanding the complex nature of bone microstructure nor to evaluate specific treatment effects on cancellous and cortical bone. Various alternatives to DXA have been developed, enabling the measurement of bone geometry and/or microarchitecture and/or bone strength including hip strength analysis, peripheral and central QCT, 3D analyses of iliac crest bone biopsies, and more recently HR-pQCT, which allows longitudinal assessment of bone microstructure at the distal radius and tibia. The efficacy of treatments for osteoporosis can be evaluated using these techniques. A true improvement of bone microstructure above baseline has not been demonstrated with anti-resorptive treatments; however, they may prevent the decay of cancellous bone and, potentially, cortical thinning. Anabolic agents such as parathyroid hormone (PTH) increase cancellous bone volume and cortical thickness; however, the improvement of cortical bone strength by PTH may be limited by an increase in cortical porosity. Strontium ranelate has been shown to improve not only the trabecular network but also cortical thickness, contributing to its anti-fracture efficacy at vertebral, non-vertebral, and hip sites.