Central dual-energy x-ray absorptiometry (DXA) has been the foundation for monitoring patients with osteoporosis. Monitoring is useful for following the effects of diseases that may negatively affect bone, such as primary hyper-parathyroidism; of drugs that may negatively affect bone, such as glucocorticoids; and of pharmacological agents for the treatment of postmenopausal osteoporosis (PMO).

Although there has been widespread acceptance of the use of bone mineral density (BMD) for monitoring disease states or in patients who are taking drugs that may cause bone loss (such as glucocorticoids) [1, 2, 3,4], there has been much debate regarding the utility of BMD to monitor the pharmacological response to osteoporosis therapies [5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15]. The debate has focused on the contribution that pharmacologically mediated changes in BMD make to a reduction in fracture risk. The use of the change in BMD as a surrogate marker for a change in bone strength is clouded by the fact that the increase in BMD mediated by current osteoporosis treatments as it relates to reduction in fracture risk is neither linear nor proportional and by the statistical methods applied to examine the relationship between BMD change and fracture risk reduction. Summary statistics (metaanalysis) [10] (Fig. 4.1) have suggested that this relationship is closer to being linear than the nonlinear relationship defined by individual clinical trial analysis defined by Freedman et al. [14, 15] (Table 4.1). In addition, the U.S. Surgeon General’s report on America’s bone health has stated that surrogate markers can be used within the context of clinical trials to reflect drug-induced improvements in bone strength. Finally, the Food and Drug Administration (FDA) approval of intermittent bisphosphonate dosing intervals (weekly, monthly, quarterly) has been allowed, based on the trust that changes in BMD reflect equal fracture risk reduction as compared with the daily dosing regimens, which were required to prove fracture reduction (“bridging concept”) [16, 17, 18,19]. Nevertheless, other factors lead to fracture risk reduction mediated by osteoporosis-specific pharmacological agents independent of change in BMD [20, 21, 22,23]. In
addition, head-to-head randomized studies, either comparing BMD changes of alendronate to that of risedronate or alendronate to that of teriparatide, have no prospective fracture data to know if differences in BMD increase render a bone stronger [24, 25].

Therefore, the debate continues regarding the value of measuring change in DXA-derived BMD as a surrogate marker for fracture risk. This debate, mostly driven by marketing, has clouded the value of BMD monitoring in patients being treated for osteoporosis. Without measuring BMD over time, patients would never receive any feedback to determine if their long-term therapy of an often asymptomatic condition is worth their commitment and
expense. In addition, the discovery of a loss in BMD beyond the in vivo least significant change [26, 27] should never become an acceptable standard of care in the management of the osteoporosis patient on treatment. A loss in BMD cannot be assumed to reflect a residual improvement in bone strength [28, 29]. A loss of BMD may be due to poor patient compliance or adherence to treatment, or to previously unrecognized and possibly reversible secondary conditions that may be responsible for a loss of BMD (e.g., celiac disease). A loss in BMD may be reversed by providing an alternative route of administration (e.g., an intravenous or transdermal or subcutaneous route of administration) or a change in pharmacological agents [30, 31,32].