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Paget's disease (PD) of the bone is a disorder where the turn over or 'remodelling' of the bone happens at a much faster and in a more uncontrolled manor than that of unaffected patients. First described by Sir James Paget in 1877 as osteitis deformans, the disease causes the bone in localised areas of the skeleton to be much larger, less compact, more vascular and therefore far weaker structurally.
To understand how the disease affects the bone, first we need to review how bone remodelling in a normal and unaffected person takes place. Bone is a dynamic tissue of the body and is constantly being turned over. This allows blood calcium levels to be maintained and the structure of the bone to be kept rigid. This task is carried out by the Basic Multicellular Unit (BMU) of the bone. The BMU is made from 2 types of cell, the osteoblast and the osteoclast. First, the calcium in the bone is reabsorbed into the blood. The osteoclast cells sit below the periosteum on the bone matrix and release hydrogen ions and lysosomal enzymes to breaking down the matrix and releasing calcium and phosphate into the extracellular fluid. Osteoblasts follow the osteoclasts, replacing any reabsorbed bone with new osetoid. This osteoid will form part of an osteon, a cylindrical structure in the bone made from tightly packed layers or lamella. These lamella are laid down in a very ordered fashion to keep the bone as compact and rigid as possible. This process happens all of the body, with around 700mg Ca2+ being replaced every day.
In PD, the bone resorption happens at a much faster rate. The osteoclasts are more abundant and much larger than normal. The osteoclasts involved in resorption will normally have between 3 and 10 nuclei per cell. These cells in patients suffering from PD can have up to 100 nuclei per cell. This increase in number and change in physiology in the osteoclasts lead to an increase in the number of osteoblasts to compensate. These cells are physiologically the same as in normal patients, but the increase in number and work rate cause the osteoblasts to lay down new osteon in an unorganised way, leading to much weaker 'woven' bone. A comparison between normal and woven bone can be seen below in figure 1. This mosaic pattern of the cement lines in the newly laid bone is the tell tale sign of PD.
PD can be diagnosed using 3 methods. Firstly, the obvious symptoms such as fractures and deformity can be observed in a patient, but as these symptoms are observed in only the most severe cases, other techniques must be used. Radiological methods such as plain radiography or scintigraph allow the extent and progression of the disease to be monitored by looking directly for the affected bone in the patient. Finally, biochemical methods can be used. As the turnover of bone in PD sufferers is much higher than in normal patients, monitoring the levels of bone specific Alkaline Phosphotase activity can reveal the disease, as to can measuring the levels of both deoxypyridinoline and N -telopeptide of type I collagen, although if the disease is confined to a small area of the body, these tests may not be as affective.
Affecting around 2-3% of people over 60 years old, the vast majority of patients are asymptomatic. Only 10-15% of sufferers of PD show severe symptoms such as pain in the affected bone, increased likelihood of fractures, deafness and deformity of the bone, such as bowing of the long bones. The disease can affect any bone in the body, although the skull, long bones, clavicle and vertebrae are the most commonly affected. PD rarely spreads between bones, instead untreated lesions simply become bigger.
Although the exact aetiology of PD is unknown, the two suggested and most researched causes are viral and genetic. Upon examination, around 40% of PD sufferers have a first degree relative who has also been affected, suggesting a strong link between autosomal dominant inheritance and the disease, linked to a genetic locus on 18q. This is a region close the Familial expansile osetolysis (FEO) locus. FEO is a PD related condition that has a much earlier onset and is known to be involved with mutations in the TNFRSF11A gene coding for receptor activator of nuclear factor kB (RANK), although other studies have only shown a loose connection between this locus and PD in most families.
The osteoclast precursors are known to be hyperresponsive to both RANKL and TNF-a, and after a genome wide study of patients with the disease, mutations in a gene encoding sequestosome coding for a scaffold protein involved in their signalling was identified. The p62 protein coded by the sequestosome 1 has many different structural regions including the ubiquitin-associated domain and SH2 and TRAF6 binding domains. At least 21 different mutations in SQSTM1/p62 on chromosome 5q have been noted, with the P392L proline-leucine codon mutation being the most common. Other mutations on the highly conserved UBA domain of SQSTM1/p62 are also associated with PD osteoclasts. The role of this mutation however is unknown, as there has been no correlation between different mutations and the severity of the disease.
The PD affected osteoclast precursor cells are also much more sensitive to Vitamin D3, due to the increased amount of vitamin D receptor coactivator, TAF12, activated be levels between 100-1000 times lower than normal. They also produce and secrete more interleukin-6 (IL-6) and express more IL-6 receptor. IL-6 stimulates the formation of osteoclasts, and can act in a paracrine manner.
Measles virus and other paramyxoviruses are also thought to be involved with PD. Around 70% of osteoclasts from PD sufferers contained Measles Virus Nucleocaspid Protein (MVNP) as well as around 90% of osteoclasts containing Measles virus mRNA.
Osteoclasts containing both MVNP and the P392L mutation have been observed to be hyperresponsive to RANKL, vitamin D3 and show high levels of TAF12, whereas cells containing only the P392L mutation show a regular response to vitamin D3, normal levels of TAF12 and a normal ratio of nuclei per cell. Both osteoclasts MVNP+/- are found to be hyperresponsive to RANKL. Cells with only MVNP present and no mutation on P329L can still form osteoclasts showing the abnormalities of PD, suggesting that only the expression of MVNP is needed to develop PD.
As the main cause of the symptoms of PD is the increased rate of bone turnover, inhibiting the osteoclasts is the main target of the most effective treatments. A variety of different bisphosphonates have been developed, each with a different action, blocking different pathways in the osteoclasts metabolism. When in the body, they become attached to the hydroxyapatite crystals in the bone, conveniently being most attracted the surfaces undergoing active resorption and therefore more likely to be absorbed by the PD affected osteoclasts. Bisphosphonates can have 2 actions in an osteoclast cell depending on their exact composition. Ones containing nitrogen based side-chains inhibit enzymes involved in the mevalonate pathway. This pathway has many actions including cell membrane maintenance and steroid biosynthesis, and interrupting it can trigger apoptosis in the effected osteoclasts. Other, non nitrogen containing bisphosphonates have similar effects on an osteoclast, binding to ATP and again interrupting metabolic pathways to cause programmed cell death. Orally administered bisphosphonates such as tiludronate and risedronate are often used in the long term management of PD.
In the body, the 32 amino acid peptide Calcitonin is produced by the C cells of the thyroid gland. It can bind directly to specific receptors on osteoclast cells to inhibit their activity and slow bone resorption, as well as lowering blood calcium levels by increasing the amount lost in urine. Calcitonin was formerly used to manage PD before the development of bisphosphonates, but due to its very short action and possible side effects depending on method of administration, it is now rarely used.
Paget's disease of the bone is a very complex disorder, in which not all the causes for its development are understood. Possible links to genetic and viral interactions have been researched and discussed, but further experimentation into their exact relation needs to be carried out before the exact aetiology of the disease can be determined.