Pagets disease of bone

2013-04-01   Stuart H Ralston 

Rheumatic Diseases Unit, Institute of Genetics, Molecular Medicine, University of Edinburgh, Scotland



Pagets disease of bone


osteitis deformans


Autosomal dominant; polygenic.






329475 Spastic paraplegia - Paget disease of bone





A family history is found in approximately 15% of cases. In such families, the disease is inherited as an autosomal dominant trait with about 80-90% penetrance by the age of 70. About 50% of patients with familial PDB have a mutation in the SQSTM1 gene and in others there is linkage to a locus on chromosome 10p13 (Lucas et al., 2008). The gene responsible in this locus remains to be identified. There also may be familial clustering without a clear patten of inheritance consistent with polygenic inheritance. Common genetic variants at seven loci have been identified that predispose to Pagets disease (Albagha et al., 2011; Albagha et al., 2010), but the causal variants have not been identified. Overall relatives of patients with Pagets have 7-fold increase risk of developing the disease as compared with the general population.

Phenotype and clinics

The disease is characterised by focal bone lesions in which there is increased osteoclastic bone resorption coupled with increase and disorganised new bone formation (Ralston, 2013). The axial skeleton is predominantly affected. The most common sites are the pelvis, spine, femurs, skull and tibia. Many patients are asyptomatic and a common mode of presentation is with an abnormal serum alkaline phosphatase picked up on routine blood tests or an abnormal radiograph. The most common complaint in patients who come to medical attention is bone pain. Other common complications include pathological fractures, bone deformity, deafness (when the base of the skull is involved), secondary osteoarthritis, and nerve compression syndromes (van Staa et al., 2002). Rare complications include hypercalcaemia which can occur if the patient is immobilised and dehydrated and high output cardiac failure due to increased blood flow through affected bone.

Neoplastic risk

The risk of osteosarcoma is increased and it has been estimated to occur in about 0.3% of patients (Mangham et al., 2009). This represents more than one thousand fold increase in risk as compared with adults in the general population (van Staa et al., 2002). The osteosarcoma arises in affected bones.


Pagets disease can be treated with bisphosphonates which supress the elevated bone turnover and can improve pain. Orthopaedic surgery may be required for the treatment of fractures, secondary osteoarthritis and spinal stenosis. Surgical excision and chemotherapy may be required for osteosarcoma.


Bisphosphonates are often effective at helping bone pain but it is uncertain at present if they alter the natural history of Pagets or prevent complications. The prognosis is poor for patients who develop osteosarcoma, even with agressive treatment (Sharma et al., 2005).



No cytogenetic abnormalities have been identified in Pagets.

Cancer cytog

Multiple chromosomal abberations have been described in osteosarcoma, but none are specific for Pagets disease.

Genes involved and Proteins


The human gene contains 8 exons and spans 31.6 Kb of genomic DNA. There are three mRNA transcripts. The predominant transcript is NM_003900 which comprises 2923 bp. Two other transcripts have been identified. One (NM_001142298.1) of 2931 bp differs from NM_003900 in the 5 UTR, lacks a portion of the 5 coding region, and initiates translation from an in-frame downstream start codon compared to another variant 1. This results in an isoform with a shorter N-terminus compared to NM_003900. A third transcript (NM_001142299) of 2848 bp differs from NM_001142298.1 in the 5UTR, but encodes the same protein isoform.


The p62 protein contains 440 amino acids and has a mass of 47 Kda. It contains several domains, uncluding a TRAF-6 binding domain, a ubiquitin associated domain and SH2 domains.


Widely expressed in many cells and tissues.


The p62 protein is an adaptor protein involved in NFkB signalling downstream of the RANK receptor, TNF receptor, IL-1 receptor and NGF receptor. In RANK signaling is responsible for recruiting CYLD to the intracellular receptor complex and this requires a functional UBA domain.


More than 25 mutations of SQSTM1 have been described in Patients with Pagets disease and most of these affect the UBA domain (Ralston and Layfield, 2012). Functional analysis indicates that most mutations impair the ability of the UBA domain to bind ubiquitin chains (Goode and Layfield, 2010).


Pubmed IDLast YearTitleAuthors
216233752011Genome-wide association identifies three new susceptibility loci for Paget's disease of bone.Albagha OM et al
198585272010Recent advances in understanding the molecular basis of Paget disease of bone.Goode A et al
179079222008Identification of a major locus for Paget's disease on chromosome 10p13 in families of British descent.Lucas GJ et al
190640072009Sarcoma arising in Paget's disease of bone: declining incidence and increasing age at presentation.Mangham DC et al
225439252012Pathogenesis of Paget disease of bone.Ralston SH et al
234060292013Clinical practice. Paget's disease of bone.Ralston SH et al
160945412005Sarcomatous change in the Pagetoid tibiae.Sharma H et al
118783052002Incidence and natural history of Paget's disease of bone in England and Wales.van Staa TP et al