Paget's disease is prevalent in certain countries - England, Spain, Germany and other regions of Western Europe - but quite rare in others such as Scandinavia and Asian nations. In the countries where Paget's disease prevails, 3% of the population may be affected, increasing to 8-9% in aged individuals. In these countries as well, Paget's disease may show geographic variations and may be found in families over a generation or more.
All of these observations have led to the theory that both genetic and environmental factors play a role in Paget's disease. Food and life-style factors have not been shown to contribute to the development of Paget's disease, but these factors could influence the health of the rest of the skeleton.
Genetics
Patients with Paget's disease frequently have a family member who also has the disease - for example, one study found 20% of patients had relatives with Paget's. Some genes are found more frequently than expected in these patients, but no single mutation has been consistently found. One of the mutated genes is for a protein called sequestosome, which might interact with other proteins (one is called ubiquitin) with resulting increased osteoclast activity. Another newly described mutation also results in abnormalities of ubiquitin. It is interesting that these same disturbances in metabolism may cause other diseases of aging, resulting in intranuclear inclusions and regional dysfunction in muscle (inclusion body myopathy) and brain (some forms of dementia). At this time the genetics of Paget's disease is not really understood, and medical researchers are actively researching this topic.
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Viral infections The osteoclasts in the diseased bones in patients with Paget's disease have microscopic particles that resemble viruses, such as measles and canine distemper. Some RNA from viruses has also been found, but not all scientists agree with these findings. It is possible that patients with a genetic predisposition will develop Paget's disease if they encounter certain viruses. Bone microenvironment The local blood supply, biomechanical stress, or marrow proteins inside the bone play a role in determining why Paget's disease in that bone is lytic (thin, too little bone) or sclerotic (dense, too much bone). | 
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The cell responsible for driving Paget's disease is the osteoclast, the cell that resorbs bone. Pagetic osteoclasts are abnormally large and active, with too many nuclei; the biochemistry is also abnormal and there are abnormal intranuclear inclusions often found in these cells. The increased bone resorption then stimulates increased bone formation, and the rapidly formed bone does not have the precise layers of normal bone. Instead, the collagen is disorganized and woven as in a fracture callus.
Animations
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Click on the star for details about the animations and the differences between Pagetic and normal bone.
A decade ago treatment for Paget's disease was only partly effective, but now a new category of medications called bisphosphonates has been developed. Bisphosphonates work directly on the osteoclasts to slow the bone resorption, and this decreases the pain in almost all patients with Paget's disease. The arthritis that is often present at the involved site may also need treatment.
It is important that patients also take adequate amounts of calcium and vitamin D to reduce the chances of osteoporosis and osteomalacia complicating the Paget's disease.
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Details
Did you notice these features of Pagetic bone?
The animation is based on histomorphometric reports by Meunier and Reid. In Paget's disease, there is more bone volume (average 42% of the area). The bone is disorganized (represented by the "sloppy" white marks in the bone) and looks woven under polarized light. The bone forms in small patches with scalloped contours, prominent cement lines give a mosaic appearance. The osteoclasts can drill through the double labels. The overall bone turnover is so high that bone does not have a chance to mineralize as densely (represented by the lighter green color). The osteoid occupies more of the surface of the bone (average 50%) but is thinner than normal osteoid. There are many more osteoclasts and fibrosis (not shown in the animations). The eroded surfaces cover an average of 23% of the surface and the average depth of resorpion cavities is 58 micrometers. The bone is resorbed very rapidly, initially at about 10 to 15 micrometers/day. Bone formation is also twice as rapid as normal, at 1.3 micrometers/day. About 80% of the osteoid surfaces show tetracycline labels. For the animation, each frame is 1.5 square millimeters, about the area seen under the microscope. There are 99 frames that cover 30 months of time, so each frame represents 9 days. The drawings and the timings are all drawn to scale. The images were measured about every ten frames to see if the surfaces and areas were within the ranges found from biopsies of patients with Paget's disease. For example, on the last frame the bone area is 54%, the osteoid surface 45% and the eroded surface 17%. |
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