In clinical trials conducted in postmenopausal women with osteoporosis, reductions in fracture risk of up to 70% in the spine, 40% in the hip and 1520% at non-hip non-vertebral sites have been demonstrated. The limited efficacy at non-vertebral sites is a concern, given the high burden and cost of these fractures. Whilst poor adherence to therapy and continuing falls risk are likely to contribute to the small effect on non-vertebral fractures, drug-specific factors may also operate. Investigation of approved and investigational drugs with differing mechanisms of action, together with improved methods for studying cortical bone structure has provided some new insights into mechanisms by which drugs may influence cortical bone strength.
A number of limitations in the assessment of cortical bone structure and strength should be recognised. First, effects of drugs on cortical bone may vary according to skeletal location. Secondly, even at a particular site, for example the femoral head and neck, there is marked heterogeneity of structure and strength and effects of drugs may be focal. Thirdly, many of the current methods for in vivo assessment of cortical bone are limited by inadequate resolution leading to difficulties in accurately assessing cortical porosity. Finally, other characteristics of cortical bone, for example the degree of mineralization and its homogeneity, and the structure of the mineral/matrix composite may affect estimates of cortical bone structure and strength.
Notwithstanding these limitations, clinical trials of approved and investigational drugs have indicated interesting differences in effects on cortical bone. Whilst bisphosphonates reduce or prevent age-related deterioration of cortical bone structure and strength, denosumab appears to increase cortical thickness, perhaps as a result of its greater accessibility to intracortical bone. The effect of parathyroid hormone peptides is variable and influenced by mechanical loading. Cathepsin K inhibitors and sclerostin inhibitors, which uncouple bone remodeling by distinct mechanisms may have greater osteoanabolic effects on cortical bone although whether this translates into greater efficacy in reducing non-vertebral fractures remains to be established.