How Anatomical “Artifacts” are Leading to Novel Treatments for Osteoporosis

One approach to preventing bone loss in postmenopausal osteoporosis is to suppress bone remodeling. However, bone remodeling is also used to repair microscopic bone damage that occurs as a consequence of skeletal loading. Suppressing bone loss by suppressing bone remodeling will allow microdamage to accumulate and raise the risk for fracture rather than lowering it. Selective estrogen receptor modulators (SERMs) are mild suppressors of bone remodeling, but reduce fracture risk nearly as much as more potent inhibitors. The mechanism for this has been unclear, but recently, using 3D ultrashort echo time MRI of devitalized bone we discovered that the SERM raloxifene increases water content in the bound water fraction of bone. Atomic force microscopy shows swelling of the collagen fibrils, and synchrotron wide and small angle X‐ray scattering shows that the localization of water between the collagen fibril and the mineral in bone allows these phases of bone to slide along one another to reduce stress and delay fracture. Interestingly, the process by which raloxifene increases water in the bound fraction is purely physical and does not require living cells. These results open avenues to engineering of new compounds that do not act through cellular processes, but specifically target the mineral and collagen interface to increase hydration and energy absorption and reduce fracture risk.