Biomechanical mechanisms: resolving the apparent conundrum of why individuals with type II diabetes show increased fracture incidence despite having normal BMD.

The article in this issue of the Journal of Bone and Mineral Research by Farr and colleagues highlights how clinical technologies enable our ability to identify biomechanical mechanisms contributing tomusculoskeletal health and disease. Given that fractures are a mechanical event, establishing biomechanical mechanisms is as important as establishing molecular mechanisms to advance our understanding of how a disease condition ultimately leads to increased risk of fracturing. As noted by Farr and colleagues, many investigators consider the increased fracture risk of type II diabetic (T2D) patients to be a conundrum, given that these individuals tend to show normal or higher bone mineral density (BMD). This would be considered a conundrum if one believes there is only a single pathway leading to increased risk of fracturing. However, we now know that reduced fracture resistance can arise through many different pathways (Fig. 1). Themost familiar pathway to reduced strength is through low bone mass resulting from an imbalance between bone resorption and formation. However, there are pathways that are less well recognized but equally important, and these come through alterations in bone morphology (eg, neck shaft angle, cortical thickness, trabecular bone volume fraction [BV/TV], trabecular connectivity) or tissue‐level mechanical properties (eg, strength, brittleness, toughness, fatigability). BMD will continue to be an important screening tool for fracture risk. However, it is too much to ask that any one technology capture all biological and biomechanical pathways leading to fracture risk. As such, it is important to continue developing new tools and scientific approaches that advance our ability to differentially diagnose fracture risk on an individualized basis. The systematic evaluation of morphological and tissue‐level mechanical properties presented by Farr and colleagues allows for a more precise and expanded definition of fracture risk. Differentiating among these pathways is critical for developing the treatment options needed to best improve bone strength for a particular disease condition. For example, some individuals may fracture because of excessive bone loss leading to measurable decreases in bone strength, whereas other individuals may fracture because changes in the extracellular matrix lead to decreases in tissue‐level toughness; these individuals would need to be differentially diagnosed and treated: one to slow bone loss and the other to improve tissue‐quality. As a field, we have not yet developed the tools and scientific background to differentially diagnose and treat individuals. However, the article by Farr and colleagues certainly moves the concept of personalized medicine one step forward. Farr and colleagues studied 30 postmenopausal womenwho had T2D for 10 or more years and 30 age‐matched postmenopausal nondiabetic controls. The study cohort showed no difference in BMD at the hip, wrist, and spine, and no difference in fracturehistory. They found substantial changes (32% to38%) in corticalporosityat thedistal radius, consistentwithother studies. However, the study by Farr and colleagues was not powered to detect a difference in this particular parameter, which is also a major contributor to tissue‐level mechanical strength. They found no deleterious changes in bonemorphology, but did find a 10.5% change (adjusted for body mass index [BMI]) in tissue‐level mechanical properties. Thus, by systematically evaluatingmultiple imaging and materials testing modalities, they were able to arrive at a biomechanical mechanism explaining why individuals with T2D may be at increased risk of fracturing. For T2D, the biomechanical mechanism is thought to be a consequence of reduced tissue toughness resulting from changes in collagen cross‐linking. The in vivo results of Farr and colleagues thus confirmed prior animal and ex vivo human research showing that T2D is indeed associated with matrix‐level alterations that appear to make the bone more damageable and brittle. Farr and colleagues reported changes in a parameter called bone material strength (BMS), which is the name given to the outcome measure by the manufacturer of the in vivo microindentation device. This outcome measure requires some clarification, because the BMS parameter seems to be more related to tissue toughness rather than tissue strength, as measured through traditional mechanical testing procedures. The device used by Farr and colleagues (OsteoProbe) and its predecessor (BioDent), both marketed by ActiveLife Scientific, Inc. (Santa Barbara, CA, USA), were designed to assess cracking of