Micrograph showing Paget's disease of the bone with the characteristic jigsaw puzzle-like/mosaic pattern, H&E stain The pathogenesis of Paget's disease is described in four stages: # Osteoclastic activity # Mixed osteoclastic – osteoblastic activity # Osteoblastic activity # Malignant degeneration Initially, there is a marked increase in the rate of bone resorption in localized areas, caused by large and numerous osteoclasts. These localized areas of pathological destruction of bone tissue (osteolysis) are seen radiologically as an advancing lytic wedge in long bones or the skull. When this occurs in the skull, it is called osteoporosis circumscripta. The osteolysis is followed by a compensatory increase in bone formation induced by the bone-forming cells, called osteoblasts, that are recruited to the area. This is associated with accelerated deposition of lamellar bone in a disorganized fashion. This intense cellular activity produces a chaotic picture of trabecular bone ("mosaic" pattern), rather than the normal linear lamellar pattern. The resorbed bone is replaced and the marrow spaces are filled by an excess of fibrous connective tissue with a marked increase in blood vessels, causing the bone to become hypervascular. The bone hypercellularity may then diminish, leaving a dense "pagetic bone," also known as burned-out Paget's disease. A later phase of the disease is characterized by the replacement of normal bone marrow with highly vascular fibrous tissue. Sir James Paget first suggested the disease was due to an inflammatory process. Some evidence suggests that a paramyxovirus infection is the underlying cause of Paget's disease, which may support the possible role of inflammation in the pathogenesis. However, no infectious virus has yet been isolated as a causative agent, and other evidence suggests an intrinsic hyperresponsive reaction to vitamin D and RANK ligand is the cause. Further research is therefore necessary.
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