Clinical and Genetic Advances in Paget’s Disease of Bone: a Review

Abstract

Paget’s disease of bone (PDB) is the second most common metabolic bone disorder, after osteoporosis. It is characterised by focal areas of increased and disorganised bone turnover, coupled with increased bone formation. This disease usually appears in the late stages of life, being slightly more frequent in men than in women. It has been reported worldwide, but primarily affects individuals of British descent. Majority of PDB patients are asymptomatic, but clinical manifestations include pain, bone deformity and complications, like pathological fractures and deafness. The causes of the disease are poorly understood and it is considered as a complex trait, combining genetic predisposition with environmental factors. Linkage analysis identified SQSTM1, at chromosome 5q35, as directly related to the disease. A number of mutations in this gene have been reported, pP392L being the most common variant among different populations. Most of these variants affect the ubiquitin-associated (UBA) domain of the protein, which is involved in autophagy processes. Genome-wide association studies enlarged the number of loci associated with PDB, and further fine-mapping studies, combined with functional analysis, identified OPTN and RIN3 as causal genes for Paget’s disease. A combination of risk alleles identified by genome-wide association studies led to the development of a score to predict disease severity, which could improve the management of the disease. Further studies need to be conducted to elucidate other important aspects of the trait, such as its focal nature and the epidemiological changes found in some populations. In this review, we summarize the clinical characteristics of the disease and the latest genetic advances to identify susceptibility genes. We also list current available treatments and prospective options.

Paget's disease of jaw bones as primary manifestation: A case report of a proper diagnosis made by general dentist

“…Cases of polyostotic or monostotic disease of mandible have been rarely described; as in the current case, the majority of people affected by mandibular PBD are over 50 years old. The jaws are involved in less than 15% of cases, with a ratio maxilla/mandible of 2/1 …”

“…There are three phases classically described, with the first being predominated by osteoclastic activity (lytic), followed by an osteoblastic as well as osteoclastic activity (mixed) and a sclerotic/blastic one (late inactive), leading to weaker and disorganised bone and more blatant clinical manifestation such as articular and/or bone pain, bones bending or bowing, cranial deformities, fractures, neurological complications like deafness, cranial nerve paralysis or spinal cord compression …”

“…However, several markers for bone turnover may prove to be useful, such as total alkaline phosphatase (ALP), pro collagen type 1 amino‐terminal propeptide (P1NP), bone‐specific alkaline phosphatase (bone ALP) and C‐terminal telopeptide (CTX) …”

“…Diagnosis of PDB is often fortuitous, usually prompted by the occurrence of certain radiographic changes, or by incidental finding of elevated level of alkaline phosphatase in an otherwise healthy individual. Genetic tests may be useful, especially in identifying specific regions of chromosome 5 and 6 both in familial or spontaneous PDB, such as RANK and SQSTM1 genes …”

Diagnostic Aspects of Paget’s Disease of Bone in Clinical Practice

“…При множест-венном поражении костей наблюдается тенденция к пра-востороннему вовлечению опорно-двигательного аппара-та [7]. У многих пациентов КБП протекает бессимптомно и выявляется случайно при обнаружении высокой актив-ности щелочной фосфатазы (ЩФ) в сыворотке крови или при рентгенологическом исследовании костей по поводу каких-либо патологических процессов [5,8,9].…”