1.2 The Bone Remodeling Cycle & Molecular Regulation
Key Takeaways
A BMU is the group of cells that remodels existing tissue. The newly formed packet or osteon is a product of that process.
Resorption and subsequent formation are coupled in sequence. A site may be incompletely refilled.
RANKL activates RANK. OPG binds RANKL and limits the signal, and denosumab targets RANKL.
Sclerostin inhibits Wnt signaling. Romosozumab targets sclerostin and increases formation while decreasing resorption.
Distinguish modeling and remodeling
Modeling changes bone shape or size through formation or resorption that need not be paired at the same surface. It contributes to growth and can continue during adult skeletal adaptation. Remodeling renews existing tissue through sequential resorption and formation. A basic multicellular unit (BMU) is the local group of cells carrying out remodeling. Its work can leave a secondary osteon in cortical bone or a packet on a trabecular surface.
In cortical bone, a cutting front can extend through mineralized tissue. Formation behind the front deposits lamellae around a central canal. On a trabecular surface, resorption can excavate an open cavity that is subsequently refilled. Neither arrangement implies a fixed number of cells, depth or speed. Coupling refers to the link between resorption and subsequent formation. The amount formed can differ from the amount removed.
| Stage | What changes at the site |
|---|---|
| Quiescence | Lining cells cover resting surfaces. |
| Activation | Local and systemic signals promote recruitment and differentiation of resorbing cells. Experimental fatigue damage can initiate targeted remodeling near the damage site. |
| Resorption | Osteoclasts dissolve mineral and degrade matrix in an enclosed compartment. |
| Reversal | The site transitions toward formation. Human histology supports an important role for osteoblast-lineage reversal cells and recruitment of osteoprogenitors. Resorption and reversal activity can overlap. |
| Formation and mineralization | Osteoblasts deposit osteoid, which begins to mineralize and can continue to gain mineral as the tissue matures. Timing varies with the site and condition. |
Formation and subsequent mineral accrual generally take longer than the initial resorption. Consider a simplified set of remodeling sites. Each cavity has had tissue removed but is only partly refilled. Starting more cavities without a corresponding increase in completed refill expands the remodeling space, the volume of cavities in progress. This can contribute to a change in measured mineral. Persistent underfilling can also cause tissue loss. A DXA difference does not determine how much came from temporary remodeling space versus lasting change, and it still needs valid serial measurement and clinical context.
Human reversal-surface studies show that cells at these sites can have osteoblast-lineage features before new matrix is deposited. Experimental work also shows that resorption can release matrix-associated signals such as TGF-β that influence progenitor recruitment. These data support multiple interacting routes for coupling. No single cell type or clock determines how quickly an individual site completes a cycle.
Follow two signaling pathways
RANKL, RANK and OPG. RANKL binds RANK on osteoclast-lineage cells and promotes osteoclast differentiation, function and survival. M-CSF also supports precursor survival and development. Intracellular pathways downstream of RANK include NF-κB and NFATc1. Osteoprotegerin (OPG) is a decoy receptor that binds RANKL and reduces access to RANK. Osteocytes are an important source of RANKL for adult remodeling in mouse experiments. Other cellular sources contribute in different settings. The relative signaling balance matters locally. It is not a clinical serum ratio used to classify an individual's DXA.
Denosumab binds RANKL and inhibits its interaction with RANK. That target helps explain reduced resorption. The drug's effects reverse after discontinuation. For treatment planning, see monitoring and therapy changes.
Canonical Wnt signaling. Wnt ligands signal through Frizzled with LRP5 or LRP6. Pathway activation stabilizes β-catenin, which influences transcription and osteoblast differentiation. In experimental osteoblasts, β-catenin can also regulate OPG expression. Sclerostin and DKK1 inhibit signaling through Wnt receptor components. Sclerostin is produced prominently by osteocytes. Romosozumab targets sclerostin and increases bone formation while decreasing resorption. Experimental pathway details describe mechanisms, while clinical effectiveness and safety require their own evidence.
Apply the distinction
Imagine that a resorption cavity initially removes 10 arbitrary units of bone volume and later receives eight units. The process is still remodeling because formation follows resorption at the site. Two units remain unfilled after the cycle. If many sites also begin resorbing at once, the temporary remodeling space can expand while the long-term deficit also grows. This illustrates why the number of new sites and the balance per completed cycle are different concepts.
Human reversal cells · Human reversal and resorption histology · TGF-β recruitment experiment · Osteocyte RANKL experiment · Osteoprotegerin discovery · β-catenin and OPG experiment · Sclerostin binding experiment · Prolia label · Evenity label
A resorption cavity loses 10 volume units and receives eight units of new bone. What can be concluded?
The process must be modeling because there is any net change.
Each completed cycle has a surplus of two units.
DXA can independently measure the number of active cavities.
This is remodeling with incomplete refill. More newly initiated cavities can also expand the temporary remodeling space.
How does denosumab act on the osteoclast regulatory pathway?
It binds RANKL and inhibits its interaction with RANK.
It activates RANK to increase osteoclast formation.
It binds sclerostin to increase Wnt signaling.
It activates alkaline phosphatase to mineralize osteoid.
Which pairing correctly links a signaling inhibitor to its targeted therapy?
M-CSF inhibition of osteoid formation and romosozumab.
Sclerostin inhibition of canonical Wnt signaling and romosozumab.
Calcitriol inhibition of RANKL and denosumab.
OPG inhibition of Wnt signaling and teriparatide.
Sections you finish are checked off in the contents.