Pagets disease of bone

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Paget's disease of bone (PDB) is one of the most common chronic skeletal diseases affecting up to 3% of many White populations over the age of 60 years. Its ethnic and geographic distribution is variable, with a high prevalence in Whites from the United Kingdom, Australia, North America and Western Europe. PDB is characterized by focal areas of increased bone resorption and formation, leading to deformity and/or enlargement. The axial skeleton (pelvis, lumbar and thoracic spine, and sacrum) is most frequently involved, followed by the femur, skull, and tibia. The newly formed bone in pagetic lesions is disorganized, frequently resulting in bowing and increased fracture. Bony overgrowth in the skull may lead to nerve entrapment, headache, and deafness.

Genetic causes of PDB are heterogeneous. Many families display autosomal dominant transmission, while in other cases only 15-40% of patients have an affected first-degree relative (Morales-Piga etal., 1995; Siris etal., 1991), or it can occur sporadically. Whole genome screens have revealed susceptibility loci on chromosomes 6p21.3 (PDB1), 18q21-q22 (PDB2), 5q35-qter (PDB3), 5q31 (PDB4), 2q36 (PDB5), 10p13 (PDB6), and 18q23 (PDB7) (Cody et al., 1997; Haslam et al., 1998; Hocking et al., 2001; Laurin et al., 2001; 2002). Of these regions, the most is known about PDB2 and PDB3. Certain forms of PDB that present under the age of 20 years are due to mutations in RANK, the osteoclast receptor for RANKL (Figure 27.1).

Table 27.2. Genes causing increased bone turnover


MIM" number

Chromosomal Gene/protein locus Phenotype

Pathogenic Inheritance mechanism

Increased bone resorption and formation Paget's disease

602080 TNFRSF11A/ 18q22.1

(167250) RANK

Juvenile Paget's disease (Idiopathic or hereditary hyperphosphatasia)

Familial expansile osteolysis

Camurati-Engelman disease




SQSTM1 or 5q35-qter p62/p62

TNFRSF11B/ 8q24.2 OPG

TNFRSF11A/ 18q22.1 RANK


High bone AD turnover, formation of abnormal bone, increased fracture risk

Same AD

Early onset, more severe form of adult Paget's

Increased NF-kB activation due to constitutive activation of RANK

Altered NF-kB

activation Unopposed osteoclast activation due to loss or dysfunction of OPG Increased NF-kB activation due to constitutive activation of RANK Enhanced TGFp stimulation of osteoblasts

" Online Mendelian Inheritance in Man (OMIM) Camurati-Engelman disease is also known as progressive diaphyseal dysplasia.

TNFRSF, TNF receptor superfamily; SQSTM1, sequestosome 1; RANK, receptor activator of NF-kB; TGFB. Transforming growth factor beta; AD, autosomal dominant; AR, autosomal recessive.

However, RANK mutations are not responsible for most cases of familial or sporadic PDB (Sparks et al., 2001; Wuyts et al., 2001), although they were reported in one Japanese family (Hughes et al., 2000). Interestingly, the gene responsible for familial expansile osteolysis, a rare disorder that overlaps phenotypically with PDB, has also been mapped to PDB2 (Hughes et al., 1994).

Mutations in the SQSTM1/p62 gene located in PDB3 have been found in patients with PDB (Hocking et al., 2002; Laurin et al., 2002). One missense mutation was found in 16% of sporadic and 46% of familial cases, but not in unaffected individuals. The gene encodes a scaffolding protein (sequestosome 1/p62) that plays an important role in several signal transduction pathways. It contains multiple interaction domains that link receptor interacting protein 1 (RIP) and TNF receptor associated factor 6 (TRAF6) with atypical protein kinase C (aPKC) isoforms that can activate an inhibitor of kappa B kinase (IKK) leading to NF-kB activation (Geetha and Wooten, 2002; Sanz et al., 1999; 2000). Importantly, TRAF6 interacts with RANK expressed on osteoclasts, and is essential for RANK-induced NF-kB activation, which in turn is important in osteoclast formation and differentiation (Figure 27.1) (Darnay et al., 1999). The precise role of p62 in RANK-mediated NF-kB activation, and whether mutations in p62 have functional significance, remains to be determined.

The pathophysiology of PDB has recently been reviewed (Roodman and Windle, 2005). There is evidence suggesting that PDB has a viral etiology (Reddy et al., 2001). Osteoclasts from patients have nuclear and cytoplasmic inclusions resembling paramyxovirus nucleocapsids. Interestingly, paramyxoviral-like nuclear inclusions have been reported in patients with familial expansile osteolysis and occasionally in other bone disorders. Their presence in a very high percentage of PDB osteoclasts has been a consistent finding, and they have even been reported in bone marrow cells. Potential connections between the genetic and viral etiologies have not been established.

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