Paget`s Disease Of The Bone (diagrams Have Been Ommitted)

Paget's disease of the bone (PDB) is the second most prevalent metabolic bone disorder in the UK, with incidence rates increasing sharply with age. It was originally described by Sir James Pagent over 130 years ago. He coined the inaccurate term 'osteitis deformans' after inadvertently categorising the condition as an inflammatory condition of the bone. However, despite vehement criticism modern scientific literature refers to the condition by this term as opposed to its correct alternative 'osteodystrophia deformans' (Rhodes, 2005). Patterns of occurrence vary from one geographical location to another. Populations originally from European ancestry (particularly Anglo-saxon) show highest rates of prevalence. These include New Zealand, Australia, South-Africa and the United States. Incidence rates as high as 3.3% have been observed in an autopsy study carried out on patients aged over 40 in the USA (Cody, 1997). Other studies based on radiological data have shown that this figure rises to about 5.4% in patients past the age of 55, suggesting a strong age dependent progression. During the past 2 decades however, studies have shown that the rate of prevalence has now decreased to levels below 2%, possibly due to early detection, clinical advances and improvements in healthcare (Whyte, 2006).

PDB is characterised by an excessive but chaotic bone remodelling, usually accompanied by morphological aberrations in the osteoclasts coupled to disorganised osteoid formation. Such disorganised growth is usually focal, affecting either one bone (monostotic) or multiple sites (polyostotic). Pagetic lesions can also affect any bone in the body, in particular the axial skeleton and bones of the extremities such as the proximal femur and (Huether et al., 2007). Since the severity and the site of a lesion may vary from one individual to another, affected persons may display diverse symptoms. For instance, involvement of the cranium causes tremendous enlargement of the skull such that vestibulocochlear nerve compression leads to tinnitus, vertigo and eventually deafness. On the other hand, if the spine is affected, patients may suffer from kyphosis i.e. increased curvature of the thoracic spine. Softening of pagetic bones also causes the femur and the tibia to become bowed as they become unable to withstand mechanical strain associated with mundane weight bearing. Conversely, most patients are asymptomatic and the disorder is clinically discovered incidentally as a radiographic finding following bone pain or fractures (Huether et al., 2007). For this reason, the diseased state of an individual may have progressed to an advanced stage such that any intervention to manage the disease may not be effective. Early diagnosis is therefore vital. Raised serum alkaline phosphates levels and urinary hydroxyproline levels are characteristic to PDB and may well be used in conjunction with radiographic analysis for the diagnosis.

The skeleton is a highly dynamic process undergoing continuous turnover, alternating between an organic and a mineral phase. This remodelling process serves as a calcium homeostasis mechanism and repairs microdamage. It is governed by the activity of two major types of cells; mononucleate osteoblasts that secrete the bone matrix and large multinucleate osteoclasts which resorb bone. In adults, this process exists as a highly regulated dynamic equilibrium divided into 4 key stages: resorptive, reversal, formative and resting/quiescent phases. During the resorptive stage, osteoclasts resulting from the fusion of mononuclear precursors (belonging to the monocyte/macrophage family) become activated. The osteoclasts consequently resorb bone in discrete cavities called Howship's lacunae by secreting protons and proteolytic enzymes (Resorption phase). Following resorption, the osteo-progenitor cells migrate to the lacunae where they are able to undergo division and differentiate into osteoblasts. Subsequently, these mononucleate cells present at the surface of mineralised bone secrete the new bone matrix (osteoid). Some of these osteoblasts gradually become trapped by the calcified bone matrix as they grow, terminally differentiating into morphologically distinct osteocytes. (Hill, 1998) Newly formed bone has a distinct lamellar structure.

In PDB, this delicate balance is disturbed. Osteoclasts lining the bony trabeculae demonstrate altered morphology such that they become abnormally large and hyperactive, consequently causing rapid resorption. An increase in osteoblastic proliferation compensates for resorbed bone immediately after the initial osteolytic phase. Once osteolysis diminishes over time, bone deposition continues in a volatile manner causing hyperostosis. From a histological point of view, pagetic bone appears larger, denser, deformed and resembles mosaic like patterns which are pathognomonic of the condition. In addition, pagetic bone becomes unsound and demonstrates elastic properties thereby resulting in bending of the femoral diaphysis described earlier. The precise aetiology of the disease however remains a debated subject.

The viral hypothesis was postulated almost 30 years ago, after ultrastructural analysis of pagetic osteoclasts revealed nuclear inclusions. These inclusions appeared microcylindrical in nature, somewhat analogous to hollow nucleocapsids of the paramyxovirus such as the Measles Virus (MV) and the Canine Distemper Virus (CDV) (Rebe et al., 2005). Biochemical analysis of pagetic bone found mRNA sequences derived from the MV; this was recreated by multiple autonomous groups. For example, studies conducted by Friedrichs et al managed to obtain a complete 1500bp mRNA transcri pt, supporting this hypothesis. On the contrary, whole virus particles have never been isolated from cultures or pagetic bone, nor has any virus specific antibody been identified from pagetic patients (Rousière et al., 2003). Moreover, nuclear inclusions are not specific to pagetic bone as they have also been reported in patients suffering from osteopetrosis, pycnodysostosis and hereditary oxalosis. For these reasons, no strong supporting argument in favour of, or against this hypothesis is conclusive enough to determine whether viral particles play a role in the aetiology of PDB.

We can safely assume that genetic factors plays an intricate role in the development of Paget's disease, since 15-40% of affected individuals have an immediate family member who also suffers from the condition (Roodman & Windle, 2005). Several possible candidate genes have been identified through gene mapping techniques. The most probable candidates have been identified as SQSTM1, TNFRSF11A, TNFSF11A and TNFRSF11B which encode P62, RANK, RANKL and OPG respectively. In order to understand how mutations in these proteins causes familial PD, the signalling pathway by which osteoclastogenesis occurs must be understood.

Recall that osteoclasts originate from the fusion of mononuclear precursor cells upon activation. During the latter half of the 1980's, Udagawa and colleagues noted that a juxtacrine signalling mechanism between committed osteoclast progenitor cells and either osteoblasts or stromal cells were necessary for osteoclast maturation, indicating surface proteins on these cells. The surface protein expressed on osteoclast progenitors is a receptor denoted RANK (Receptor Activator of Nuclear factor Kappa B). It can bind to its ligand RANKL presented to it by osteoblasts in the presence of Macrophage Colony Stimulating Factor (M-CSF) to stimulate osteoclastogenesis, cell survival and growth. Osteoprotegerin (OPG) on the other hand, is a secreted factor which inhibits osteoclastogenesis by serving as a soluble 'decoy' receptor for RANKL. The balance between levels of RANKL expression and OPG are therefore imperative to osteoclast maturation. A large number of osteotropic factors including parathyroid hormone (PTH), calcitriol and Interleukin-1 beta (IL-1?) indirectly stimulate osteoclast proliferation by causing an increased expression in the surface ligand RANKL on target cells (Roodman & Windle, 2005). Once RANKL interacts with the receptor RANK, a multitude of intracellular signalling cascades are triggered, ultimately leading to osteoclast differentiation, cell survival and growth as shown in figure 1 below. The downstream transcri ption factor, Nuclear Factor Kappa B (NF-?B) is thought to have profound importance in the process of osteoclastogenesis, since deliberate mutations in mice have resulted in thickening of bone, also characteristic to Paget's disease (Roodman & Windle, 2005).

Multiple phenotypic screenings by independent groups elucidated a potential locus on chromosome 5q35 for the gene SQSTM1 which encodes the protein sequestosome 1, also known as p62. It normally functions as a scaffold protein in the NF-?B pathway. Point mutations (particularly P392L) in the Ubiquitin Associated domain (UBA) of SQSTM1 have been associated with atleast 20% of familial and sporadic cases. Furthermore, osteoclasts in knockout mice lacking this UBA region of SQSTM1 display a hypersensitivity to RANKL. A possible explanation for this observation would be a continuous activation of the NF-?B signalling pathway simply because the mutation hinders with ubiquitin dependant proteolysis (Ralston et al., 2008). Note that not all individuals with the P392L mutation suffer from the condition, suggesting that genetic factors solely do not determine the development of the disease. Environmental factors may also be accountable for the focal nature of the disease and its late onset (Roodman & Windle, 2005).

Recently, focus has been shifted to genes encoding RANK, RANKL and OPG simply because polymorphisms in these genes are known to cause various rare disorders that share features with PDB. Inactivating mutations in the TNFRSF11B gene in Juvenile onset paget's for example, would sequentially lead to a reduced/complete loss of function of OPG which is involved in inhibiting osteoclastogenesis. As a consequence, the ratio of RANK to functional OPG is persistently high causing an increase in bone resorption. 'Insertion mutations within the first exon of TNFRSF11A gene' have been shown to interfere with the cellular localisation of the protein, possibly by disturbing cleavage of the signal peptide. Conversely, the molecular link between this observation and how it interferes with bone remodelling remains unknown (Ralston et al., 2008).

Treatment of PDB largely depends on the severity of pain experienced by the patient. Suppressive agents such as calcitonin and bisphosphonates inhibit bone resorption and are largely used to prevent the legion from spreading to an advanced stage, thereby preventing complications. Probably the most renowned of these drugs is the bisphosphonate family, which can be taken either orally or intravenously. Clinical trials have elucidated several effects of this drug which may act to improve quality of life through metabolic control of the bone. Apart from reducing bone turnover, there is increasing evidence the most potent of these drugs such as zolidronic acid can reduce pain, improve healing and restore lamellar bone. Antiresorptive therapy is usually given continuously for 3-4 months in conjunction with calcium and vitamin D. However, these drugs are not effective at reversing deformity or osteoarthritis. In such cases, orthopaedic surgery may be necessary. Also, in advanced cases analgesic agents and non-steroidal anti-inflammatory agents may be used to alleviate pain (Ralston et al, 2008). The key to preventing familial PDB from progressing to advanced stages is early diagnosis. As I mentioned earlier, the SQSTM1 mutation (amongst others) is critical to its pathology later on during life, thus detecting this mutation before symptoms appear in the future could serve useful in early intervention. Future concepts include the antiRANKL antibody, which has shown promising results in clinical trials.

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