The osteoclasts attach to the bone surface where the extracellular calcium concentration decreases

Osteoclasts demineralize and resorb bone once they attach to its surface. However, it's still unclear how the osteoclasts choose the specific sites for their attachments. It is postulated in this article that the decreased extracellular free ionized calcium concentration (Ca²⁺_[e]) can provide a microenvironment for osteoclasts to recognize and then initiate the attachment process. The osteoclasts initially attach to the bone surface via integrating its integrin α_vβ₃ and RGD containing ligands in bone matrix. Through the interaction with RGD-containing ligand, the integrin α_vβ₃ forms carboxylate oxygen noncovalent, which is further stabilized by accompanied electrostatic interaction between the Ca²⁺ and the β₃ subunit. There are two types of cation-binding sites on the β₃ subunit: the high affinity Ca²⁺ binding site ("LC" site) that activates the osteoclasts by promoting the combination; the low affinity Ca²⁺ binding site ("I" site, also named ADMIDAS) that deactivates the osteoclasts by dissociating the combination and it can override the "LC" site's positive effect on osteoclasts when necessary. Normally the Ca²⁺ concentration of bone extracellular fluid is maintained within a normal range by osteocytes, keeping the "I" sites activated. When the osteocytes' function stalls and the ambient Ca²⁺ concentration falls below the affinity discrimination threshold between the "I" site and the "LC" site, the "LC" site's promoting function starts to out compete the "I" site in its inhibitory effect, in which case the inactive integrin α_vβ₃ turns into an extended active form and the osteoclasts start to attach, signifying the initiation of bone resorption.