Etiology

Etiology is unknown at present; however, several etiologic factors have been suggested.

  • Genetics: familial clustering suggests that PDB may have an autosomal dominant pattern of inheritance with variable penetrance.[9] The relative risk of developing the condition is as high as 7 in first-degree relatives of people diagnosed with PDB.[10] Mutation in a gene called sequestosome 1 (SQSTM1) has been found in up to 50% of cases of familial PDB, and in some sporadic cases of PDB as well.[3] Familial PDB is genetically heterogeneous and several additional loci have been associated with the development of PDB (i.e., CSF1, TNFRSF11A [RANK], OPTN, and VCP).[11]

  • Infection: paramyxoviruses, such as measles virus, respiratory syncytial virus, and canine distemper virus, have been implicated in the etiology of this disease.[12][13][14][15] Electron microscopy has shown virus-like structures that resemble paramyxoviruses in pagetic osteoclasts. Over-expression of measles virus nucleocapsid protein in mice harboring a SQSTM1 mutation causes a PDB phenotype.[16] However, more recent studies have been unable to confirm the presence of paramyxovirus in bone biopsies or other tissues from patients with PDB.[17]

  • Environmental: given regional variations and the decline in disease prevalence over the past several decades, environmental factors have been hypothesized to contribute to pathogenesis. It has been speculated that high levels of arsenic or contact with cattle or dogs and other pets may be factors.[18][19] However, other studies have been unable to find such an association, and no environmental factors have consistently been associated with PDB.[20]

Pathophysiology

The main feature of PDB is localized areas of metabolic hyperactivity of bone. The primary abnormality is believed to be in the osteoclasts, which are abnormally large with excess nuclei. Pagetic osteoclasts are responsible for increased bone resorption, causing large resorption pits and cavities.[21] Bone formation is linked to resorption and, in order to compensate for the increased resorption, osteoblast activity is dramatically increased in pagetic lesions. The osteoblast activity is so rapid that newly-formed bone is not organized and remains irregular and woven in nature. The newly-formed woven bone is less resistant and more elastic than typical lamellar bone and, hence, prone to deformity and microfractures, especially in the weight-bearing extremities. There is a high degree of vascularity in the pagetoid bone, which, in conjunction with the microfractures, is thought to be the cause of pain in patients with underlying PDB of the bone.[22]

PDB evolves through three distinct phases:

  1. An initial, short-lived burst of multinucleate osteoclastic activity causing bone resorption

  2. A mixed phase of both osteoclastic and osteoblastic activity, with increased levels of bone turnover leading to deposition of structurally abnormal bone

  3. A final chronic sclerotic phase, during which bone formation outweighs bone resorption.

The continued process of excessive, abnormal bone-forming activity and creation of microfractures results in deformities, with resultant change in the biomechanical milieu of the adjacent joints. The latter, combined with old age, predisposes these patients to arthritis.[23] In the skull and spine, the resultant changes lead to a chronic nonspecific inflammation and, occasionally, narrowing of the various foramens, resulting in cranial and spinal nerve impingement. Ischemic myelitis is rarely seen; this is hypothesized to be due to the high metabolic and vascular demands of pagetoid bone, which steals the blood supply away from the nearby spinal cord and nerve roots.[24]

Classification

Degree of bony involvement

  • Monostotic: involves only one bone (femur is the most common site), and occurs in 25% of patients.[1][2]

  • Polyostotic: involves more than one bone (usually the femur, pelvis, skull, tibia, or vertebrae), and occurs in 75% of patients.[1][2]

Severity of symptoms

  • Asymptomatic: most people with PDB are asymptomatic.

  • Symptomatic: symptom severity may range from minimal bony discomfort to severe pain due to pathologic fractures, and may include other complications (e.g., secondary osteoarthritis, spinal stenosis, deafness, or other nerve compression syndromes; rarely, high output cardiac failure).[3]

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