Paget Disease of Bone

Definition

Paget disease of bone is a focal disorder of the skeleton characterized by increased and disorganized bone remodeling. Affected bones enlarge, become deformed, and are at increased risk for pathologic fractures.

Epidemiology

The prevalence of Paget disease is about 0.5% in the United Kingdom and United States. It also occurs in Western Europe and in people of European descent who have migrated to other parts of the world. Paget disease is rare in Scandinavians, Africans, and Asians. These differences are thought to have a genetic basis occurring as the result of founder mutations in northwest Europe many centuries ago, with subsequent spread to the remainder of the world through emigration. The incidence of Paget disease increases with age; in the United Kingdom, the incidence in women and men respectively is 0.037 to 0.074 per 10,000 person years in individuals ages 45 to 49 years but doubles in frequency each decade thereafter to reach an incidence of about 3.7 and 6.3 per 10,000 person years in individuals ages 85 years and older. The prevalence and severity of Paget disease have diminished in the United Kingdom and many countries over the past 25 years. Although the mechanisms are unclear, suggested explanations include the influx of migrants from low prevalence areas, improved nutrition, a more sedentary lifestyle with a reduction in skeletal injuries, and reduced exposure to infections.

Pathobiology

Susceptibility to Paget disease is strongly influenced by genetic factors, but environmental factors are also important. The importance of genetics is emphasized by the facts that between 5 and 40% of patients have a positive family history and that the risk for developing Paget disease in a first-degree relative of a patient is about seven-fold higher than in the general population. In many families, the disease is transmitted in an autosomal dominant manner, although penetrance is incomplete.

The most important susceptibility gene for classical Paget disease is SQSTM1 . Mutations of SQSTM1 are present in up to 40% of patients with a family history and 5 to 10% of people without a family history. The SQSTM1 gene encodes a protein called p62 that is involved in regulating signal transduction downstream of the receptor activator of nuclear factor κB (RANK), which plays a critical role in regulating osteoclastogenesis when activated by RANK ligand (RANKL) ( E-Fig. 228-1 ). The disease-causing mutations cluster in the ubiquitin-associated domain and have the effect of upregulating nuclear factor κB (NFκB) signaling and stimulating osteoclastogenesis by complex mechanisms that are reviewed in detail elsewhere.

Genome-wide association studies have identified seven other loci that predispose to Paget disease and that individually increase the risk between 1.4- and 1.7-fold. These loci have additive effects, such that individuals who carry several predisposing alleles have a substantially increased risk for developing Paget disease. Many lie close to genes that play key roles in osteoclast function, including CSF1 , which encodes macrophage colony-stimulating factor (M-CSF); TNFRSF11A , which encodes RANK; TM7SF4 , which encodes DC-STAMP; OPTN , which encodes optineurin; PML , which encodes a protein involved in regulating interferon signaling; and RIN3 , which encodes a guanine exchange factor that is expressed in osteoclasts (see E-Fig. 228-1 ).

Rare inherited diseases with clinical features overlapping with those of Paget disease include familial expansile osteolysis and related syndromes caused by mutations affecting the signal peptide of RANK, as well as juvenile Paget disease caused by loss of function mutations affecting osteoprotegerin. Mutations in VCP , hnRNPA2B1, hnRNPA1, PFN1, OPTN, and SQSMT , which may result in defects in the autophagy pathway, can also lead to multisystem proteinopathy where Paget disease is part of a generalized disorder in which dementia, myopathy, or amyotrophic lateral sclerosis can also occur. ^, Mutations in ZNF687 cause a form of Paget disease that is accompanied by giant cell tumors. At present, the mechanisms by which ZNF687 mutations cause this syndrome is unclear.

Bone is normally renewed and repaired in an orderly and tightly regulated fashion through the process of bone remodeling. Bone remodeling is highly abnormal in Paget disease. Osteoclasts are increased in number and size, and they are hypernucleated. Some contain nuclear inclusion bodies, which may be aggregates of undegraded proteins caused by defects in the autophagy pathway. Bone formation is markedly increased, and the amount of new bone that is formed exceeds that which is removed by osteoclastic activity, leading to enlargement and deformity of affected bones ( Fig. 228-1 ). The newly formed bone is laid down in a disorganized fashion (woven bone) and has impaired mechanical strength. Other features include increased vascularity and marrow fibrosis.

The focal nature of Paget disease remains a puzzle. Suggested explanations include the occurrence of somatic mutations in affected bones, which locally increase osteoclast activity, or excessive mechanical loading or skeletal injuries early in life, which by causing microdamage act as a focus for localized increases in bone remodeling.

Clinical Manifestations

An estimated 7 to 16% of patients with Paget disease come to medical attention, but the mode of presentation is highly variable. About 20% have no symptoms; in these subjects, Paget disease is detected as the result of a raised serum alkaline phosphatase level or an abnormal radiograph in individuals who are being investigated for another reason. In the remainder, symptoms attributable to Paget disease are observed. The most common is pain, which can be due to either increased bone turnover or to a complication such as osteoarthritis ( Chapter 241 ), spinal stenosis ( Chapter 369 ), pseudofractures, enlarged skull, bowing of long bones, or nerve compression syndromes. Deafness, which may occur in patients with skull involvement, is usually conductive rather than due to auditory nerve compression. Osteosarcoma ( Chapter 187 ) occurs in less than 0.5% of cases but should be suspected in patients who experience a sudden increase in bone pain or swelling of an affected site. Other, rare complications include obstructive hydrocephalus, high-output cardiac failure, and hypercalcemia in patients who are immobilized. The risk for cardiovascular disease is increased in patients with Paget disease compared with age- and gender-matched controls, probably owing to an increased prevalence of vascular calcification.

Most patients have no clinical signs. However, some patients present with bone deformity (see Fig. 228-1 ) or warmth of the skin overlying an affected bone.