You are likely questioning how changes at the cellular level lead to the systemic disruption of skeletal system. In healthy bone we see osteoblasts and osteoclasts working together to efficiently remodel bone, and associated with that are appropriate levels of signals leading to differentiation of these cells. In osteoporosis, there is a disruption caused by imbalanced signaling of transcription factors. 

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Let's dive into the cell! Beginning with the RANK Pathway, RankL binds to the Rank Receptor on the surface of the cell. TNF receptor associated factor 6 (Traf6) associates with this complex leading to the association of Tak1, Tab1, and Tab2 in a complex (5). This complex promotes signaling and leads to the activation of IKKs which are a complex of catalytic kinase subunits and scaffold proteins that lead to the activation of NF-kB and localization of NF-kB into the nucleus (6). The IKK complex consists of IKK-alpha and IKK-beta along with a regulatory subunit that work to phosphorylate, activate kinase subunits and localize NF-kB to the nucleus (6). The localization leads to signaling that increases the transcription factors related to osteoclast differentiation (5). 

It is suspected that increased amounts of RANKL are seen due to decreased levels of estrogen in females experiencing menopause (3). By this pathway, we see an increase in osteoclast differentiation. This is only half of the equation, however. A lack of osteoblasts also contributes to the onset of osteoporosis. 

In the Wnt Pathway, decreased differentiation of osteoblasts is as a result of decreased Wnt available for binding to initiate the cascade (7). When Wnt doesn’t bind to the Frizzled/Disheveled complex, LRP5/6 fails to associate with this complex (1, 7). In this case, B-catenin is phosphorylated by GSK-3 (glucose synthase kinase-3), which marks it for degradation (1,7). GSK-3 is part of a complex including Axin and APC (7). A proteasome degrades B-catenin, which leads to the absence of nuclear localization of B-catenin (1, 7). Normally B-catenin would enter the nucleus and displace corepressors leading to increased transcription – lack of B-catenin leads to the corepressors staying in place and no transcription (7). This illustrates how lack of Wnt leads to the inhibition of a cascade that typically results in osteoblast differentiation. 

The brittle, porous bone that results from an imbalance in remodeling is associated with the pathology in osteoporosis. This brittle bone fractures easily and in turn can lead to many complications, including difficulty in surgical repair of the fracture, infection, pain, and is associated with increasing fractures in the future (2, 4).