Paget's disease

notes by dr Claudio Italiano 

Paget's bone disease is placed among the metabolic osteopathies because it is characterized by a conspicuous alteration of the bone remodeling. As discussed below, its etiopathogenesis is not however fully clarified. Paget's bone disease occurs at an advanced age. It is a very common condition after osteoporosis. It has a long course and generally has a phase of acute, or florid phase, which can be followed by a phase of attenuation that can pass into a further florid phase. It can be localized to a single skeletal segment (monostotic forms) or to several segments (polyostotic forms), as well as starting in one segment, attenuating it and presenting itself in a florid form in another skeleton district.

Clinical picture

Clinically, the disease is characterized by the increase in volume and deformation of the affected bone segment, as well as pain, although the forms are completely rare asymptomatic. The thermotact of the affected area is high as a consequence of an increase in blood flow through the bone. Severe structural alterations such as stenosis of the cranial foramina, with compression of the nerves, severe deformations of the facial massif (so-called bone leontiasis), deafness, compression of the spinal cord, etc. can occur.
 

Paget, spongy bone, alteration of the bone trabeculae

Microscopically, the most striking finding during the florid phase is represented by the notable increase in bone remodeling, which however is extremely disordered. It is initially supported by a large increase in osteoclasts, which present an excessive number of nuclei, some of which can be pycnotic and coarctated. The equilibrium that normally exists between osteoclasts and osteoblasts is generally maintained, so that a high number of osteoblasts and an active osteogenesis with the production of a matrix of the interwoven fibers type are also observed.
This is reflected in a conspicuous increase in serum alkaline phosphatase which, together with the increased urinary finding of hydroxyproline and other collagen catabolites, which are indices of increased bone resorption, has an important diagnostic significance. However, the osteogenesis process is not spatially related to reabsorption, but occurs chaotically without any correlation with Howship loopholes. Such a disorderly process of reabsorption and repair is responsible on the one hand for a "porosity" of the bone due to the numerous unprotected osteoclastic gaps; on the other hand it determines the formation of coarse and irregular trabeculae, without connection or irregularly
connected. These findings were in the past included under the names of "hypertrophied atrophy" or "porotic hyperostosis", which still retain a descriptive meaning. Variable degrees of fibrosis and a large number of ectatic blood vessels can be observed in the medullary spaces of the spongy bone. In the compact bone of the long bones, conspicuous subperiosteal ossification occurs on the tensioned cortical slopes, which is the main cause of the increased bone volume and which can cause roughness and irregularity of the surface, up to the production of osteophytes.

At the level of the rachis it is possible to have a narrowing of the medullary canal. The neo-deposit matrix is ​​generally regularly calcified. From what has been said it is clear that, apart from the conspicuous disorder that characterizes remodeling, the bone alteration is similar to that found in severe hyperparathyroidism: a notable increase in osteoclasts and bone resorption, a more or less corresponding increase in osteogenetic activity and of osteoblasts, production of intertwined fibrous bone, fibrosis of the medullary spaces in which highly ectatic blood vessels run. The electron microscopic examination of the pagetic bone in the florid phase has allowed, however, to find some characteristic alterations. They were indeed
observed in the included nuclear and cytoplasmic osteoclasts consisting of elongated, filamentous-tubular structures, with a thickness of about 15 nm and an internal diameter of about 5-7 nm, which often arrange themselves to form paracrystalline structures.

Paget, TRAP staining, active osteoclasts in red

 They are mostly contained in the picnotic and coarctated nuclei found on histological examination, considered by some to be apoptosis. Both for their ultrastructure and for their immunohistochemical reactions, the nuclear included were considered as aggregates of paramyxovirus capsids and it was considered that Paget's bone disease could be supported by attenuated virus infection. This hypothesis appears in agreement with the fact that the bone Paget has other characteristics typical of such diseases, such as the long course, the prolonged period of clinical latency, the presence of giant polynuclear cells (osteoclasts) containing viral included, the possible familiarity of the affirmation . It has also been suggested that the viruses in question may be those of measles.

Genetic causes

 There is a hereditary factor in the development of Paget's disease of bone. Two genes, SQSTM1 and RANK, and specific regions of chromosome 5 and 6 are associated with Paget's disease of bone. Genetic causes may or may not involve a family history of Paget's disease.

About 40–50% of people with the inherited version of Paget's disease have a mutation in the gene SQSTM1, which encodes a protein, called p62, that is involved in regulating the function of osteoclasts (bone cells). However, about 10-15 percent of people that develop the disease without any family history also have a mutation in the SQSTM1 gene.

However, no definitive conclusion has been reached, either because nucleocapsids of other viruses (respiratory syncytial, murine and canine distemper) have been identified by three nucleocapsids of the measles virus, and because the same type of nucleocapsids has been found in relevant osteoclasts. to non-pagetic osteopathies, including some of genetic origin. It is possible that there is some predisposition to contract the disease, as seems to indicate the occurrence of several cases in the same family nucleus. It is interesting, but for now without explanation, the fact that the frequency of Paget's bone disease is much greater in some areas of the world (France and England in Europe, Australia and New Zealand) than in others (China, India, Malaysia) . In the United States, the disease is more common in European whites. If the florid phase of Paget's bone disease is followed by remission, there is a gradual attenuation of the degree of bone remodeling: the osteoclasts decrease in number, the depletion-absorption holes become less frequent and are repaired by the formation of new bone, the number of osteoblasts gradually normalizes. The previous florid phase, however, remains documented by the presence of numerous cementing lines, which indicate the limit at which the phase of reabsorption of the numerous and disorderly BMUs had stopped and the reversal phase had intervened and, subsequently, of repair. The result is a characteristic aspect, called "mosaic", because the numerous residual cementing lines of the disordered resorption and reconstruction activity delimit bone-like zones arranged in such a way as to remember the tesserae of a mosaic.
A fearful complication of Paget's bone disease is the appearance of an osteosarcoma, a likely consequence of the increased cell turnover. Furthermore, the development of so-called "osteoclastomas", ie benign tumors, is susceptible to recurrence, histologically constituted by numerous giant multinuclear cells which, to be positive for the TRAP reaction, belong to the osteoclastic line. They may have a variable number of coarct and pseudo nuclei, which contain the included already described in the osteoblasts.

Treatment

The goal of treatment is to relieve bone pain and prevent the progression of the disease. These medications are usually recommended for people with Paget's disease who:

- have bone pain, headache, back pain, or a nerve-related symptom (such as "shooting" pains in the leg) that is directly associated with the disease;
- have elevated levels of serum alkaline phosphatase (ALP) in their blood;
- display evidence that a bone fracture will occur;
- require pretreatment therapy for affected bones that require surgery;
- have the disease in bones located next to major joints, placing them at risk of developing osteoarthritis;
- develop hypercalcemia that occurs when a person with several bones affected by Paget's disease and a high serum alkaline phosphatase level is immobilized.
 

Bisphosphonates

Bisphosphonates are currently available. In general, the most commonly prescribed are risedronic acid, alendronic acid, and pamidronic acid. Etidronic acid and other bisphosphonates may be appropriate therapies for selected patients but are less commonly used. None of these drugs should be used by people with severe kidney disease.

Calcitonin

Calcitonin, also called calcitonin-salmon, is a synthetic copy of a polypeptide hormone secreted by the ultimobranchial gland of salmon. Miacalcin is administered by injection, three times per week or daily, for 6–18 months. Repeat courses can be given after brief rest periods. Miacalcin may be appropriate for certain patients, but is seldom used. Calcitonin is also linked to increased chance of cancer.

Surgery

Medical therapy prior to surgery helps to decrease bleeding and other complications. Patients who are having surgery should discuss treatment with their physician. There are generally three major complications of Paget's disease for which surgery may be recommended.

Surgery may allow fractures to heal in a better position. In case of severe degenerative arthritis, If disability is severe and medication and physical therapy are no longer helpful, joint replacement of the hips and knees may be considered. In to the bone deformity, cutting and realignment of pagetic bone (osteotomy) may help painful weight bearing joints, especially the knees.

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