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Pathophysiology of Paget's disease (Osteitis deformans)


*Osteoclast maturation is regulated by various factors, such as Receptor Activator of Nuclear Factor-kappaB (NF-kappaB) Ligand (RANKL). RANKL can exist as a soluble form and binds to the osteoclast receptor RANK.
*This binding activates osteoclast differentiation via the translocation of NF-kappaB into the nucleus by intermediates such as Tumor Necrosis Factor (TNF) Receptor-Associated Factor 6 (TRAF6).
*RANKL signals can be blocked by a soluble RANKL-binding decoy receptor, osteoprotegerin (OPG), produced by osteoblasts.
*Vacuolar H+-ATPase pump (H+), matrix metalloproteinase (MMP), Cathepsin K and Tartrate-Resistant Acid Phosphatase (TRAcP) are involved in osteoclast activity.

*This picture above helps us in understanding the pathophysiology behind PAGET'S disease :

- The principal abnormality in Paget disease is the increased number and activity of osteoclasts. 
- Pagetic osteoclasts are large, increased 10- to 100-fold in number, and have a greater number of nuclei (as many as 100 compared to 3–5 nuclei in the normal osteoclast). 
- The overactive osteoclasts may create a sevenfold increase in resorptive surfaces and an erosion rate of 9 microg/d (normal is 1 microg/d).
- Several causes for the increased number and activity of pagetic osteoclasts have been identified: 
(1) Osteoclastic precursors are hypersensitive to 1,25(OH)2D3
(2) Osteoclasts are hyperresponsive to RANK ligand (RANKL), the osteoclast stimulatory factor that mediates the effects of most osteotropic factors on osteoclast formation; 
(3) Marrow stromal cells from pagetic lesions have increased RANKL expression; 
(4) Osteoclast precursor recruitment is increased by interleukin (IL) 6, which is increased in the blood of patients with active Paget disease and is overexpressed in pagetic osteoclasts; 
(5) Expression of the proto-oncogene c-fos, which increases osteoclastic activity, is increased; and 
(6) The antiapoptotic oncogene Bcl-2 in pagetic bone is overexpressed. Numerous osteoblasts are recruited to active resorption sites and produce large amounts of new bone matrix. As a result, bone turnover is high and bone mass is normal or increased, not reduced.

- The characteristic feature of Paget disease is increased bone resorption accompanied by accelerated bone formation. 
- An initial osteolytic phase involves prominent bone resorption and marked hypervascularization. 
- Radiographically, this manifests as an advancing lytic wedge, or "blade of grass" lesion. 
- The second phase is a period of very active bone formation and resorption that replaces normal lamellar bone with haphazard (woven) bone. 
- The mosaic pattern of woven bone is structurally inferior and can bow and fracture more readily. 
- At the same time, fibrous connective tissue may replace normal bone marrow. 
- In the final sclerotic phase, bone resorption declines progressively and leads to a hard, dense, less vascular pagetic or mosaic bone, which represents the so-called burned-out phase of Paget disease. 
- All three phases may be present at the same time at different skeletal sites.

*Acutely marginated bone demineralization during lytic phase in skull - OSTEOPOROSIS CIRCUMSCRIPTA.
*Acutely marginated demineralization of long bones - BLADE OF GRASS SIGN and FLAME SHAPED MARGIN.
*Mixed lytic and sclerotic phase in spine - PICTURE FRAME VERTEBRAE
*Mixed lytic and sclerotic phase in skull - COTTON WOOL SKULL.

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