Advanced Pathophysiology

Paget's Disease of Bone

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Speaker 2: Paget's disease of bone is a disorder in which there's a lot of bone remodeling that happens in some regions of the bone. Typically, there's excessive bone resorption followed by excessive bone growth, and that leads to skeletal deformities and potential fractures. Normally, bones undergo a continuous process of remodeling. Old brittle bone tissue gets reabsorbed by multinucleated bone cells called osteoclasts, which have 5 to 20 nuclei per cell.

The resorbed bone tissue gets replaced by a new one made by another type of bone cell, called an osteoblast. At the cellular level, the process begins when osteoblasts release receptor activator of nuclear factor kappa beta ligand, or RANKL for short, which is a substance that binds to rank receptors on the surface of an osteoclast. When RANKL binds to the rank receptor, it activates the osteoclasts, and they start secreting lysosomal enzymes like collagenase, as well as hydrochloric acid. Together, they digest the collagen protein and dissolve the minerals that make up the bone matrix.

Once there's been sufficient bone demineralization, the osteoblasts secrete another substance called osteoprotegerin or OPG for short, which binds RANKL and prevents it from activating the rank receptors. This causes the osteoclast to stop demineralizing the bones. Once that happens, the osteoblast starts accreting a substance called osteoid seam, which is mainly made up of collagen and acts like a scaffold upon which calcium and phosphate can get deposited. And that's how new bone begins to get formed again.

The exact cause of Paget's disease of bone is unclear, but it can get triggered by infections like the measles virus, and is linked to genetic mutations like the SQSTM1 mutation, which encodes a protein involved in regulating osteoclasts. When Paget's disease of bone occurs, it can affect a single bone, or the whole skeletal system. Most often it involves the skull, lumbar vertebrae, the pelvis and the femur.

Now, there are three main phases to the disease. Phase one is the lytic phase, and that's where osteoclasts, which have up to a 100 nuclei start to aggressively demineralize the bone up to 20 times more than normal. Phase two is the mixed phase, and that's where the lytic phase occurs alongside the blastic phase. In the blastic phase, there's a rapid, but relatively disorganized proliferation of new bone tissue by an unusually large number of osteoblasts. The result is that collagen fibers are deposited in a haphazard way. Phase three is the sclerotic phase and that's where new bone formation exceeds bone resorption. And the final result is bone that's structurally disorganized, and therefore weaker than normal, healthy bone. Eventually, the osteoblastic activity also slows down and there's a dormant state in the disease, called the "burned-out state".

Early on, Paget's disease of bone doesn't typically cause symptoms, but over time, the misshapen bones can impinge on nerves and cause pain. In addition, if the skull is involved, the overgrowth of bones can make a person have a lion like face, which is called Leontiasis. The bony overgrowth can also narrow the auditory foramina and impinge on the auditory nerve leading to hearing loss.

If there's bony overgrowth that impinges on the optic nerve, as it passes through the optic canal, that can lead to vision loss. Sometimes the accelerated bony growth can lead to genetic mutations that cause a bone cancer called osteosarcoma. When that happens, it's referred to as Paget's sarcoma. Other bony deformities from Paget's disease of bone include kyphosis, which is an excessive curvature of the spine, making a person face down to the ground, lower limb muscle weakness from misshapen vertebrae compressing the spinal cord and pelvic asymmetry. It can even lead to bow legs if the femurs get too weak to support a person's weight, and they begin to bend over time. If the parts of the bone that are involved in a joint become effected, it can result in arthritis or joint inflammation.

The diagnosis of Paget's disease of bone is usually done by checking for elevated levels of alkaline phosphatase. In addition, an x-ray might show lytic lesions during the lytic phase of the disease, or thickened bone cortices in advanced cases. Finally, a bone biopsy is usually done to exclude malignancies, which can mimic some of the findings of Paget's disease of bone. Treatment of Paget's disease of bone includes pain relievers, as well as anti-resorptive medications like bisphosphonates, which slow down the bone lysis. In addition, surgery can help correct bone deformities, decompress an impinged nerve, and reduce associated fractures.

All right, as a quick recap, in Paget's disease of bone, there's an excessive amount of bone resorption and haphazard bone growth. There's a lytic phase, a mixed phase, with both the lytic and blastic component, and a sclerotic phase, which results in weak bones. Paget's disease of bone is usually asymptomatic, but can result in weak misshapen bones that cause fractures and lead to nerve compression.

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