Paget's disease is a localized bone-remodeling disorder that affects widespread, noncontiguous areas of the skeleton. The pathologic process is initiated by overactive osteoclastic bone resorption followed by a compensatory increase in osteoblastic new bone formation, resulting in a structurally disorganized mosaic of woven and lamellar bone. Pagetic bone is expanded, less compact, and more vascular; thus, it is more susceptible to deformities and fractures. Although most patients are asymptomatic, symptoms resulting directly from bony involvement (bone pain, secondary arthritis, fractures) or secondarily from the expansion of bone causing compression of surrounding neural tissue are not uncommon.
There is a marked geographic variation in the frequency of Paget's disease, with high prevalence in Western Europe (Great Britain, France, and Germany, but not Switzerland or Scandinavia) and among those who have immigrated to Australia, New Zealand, South Africa, and North and South America. The disease is rare in native populations of the Americas, Africa, Asia, and the Middle East; when it does occur, the affected subjects usually have evidence of European ancestry, supporting the migration theory. For unclear reasons, the prevalence and severity of Paget's disease are decreasing, and the age of diagnosis is increasing.
The prevalence is greater in males and increases with age. Autopsy series reveal Paget's disease in about 3% of those over age 40. Prevalence of positive skeletal radiographs in patients over age 55 is 2.5% for men and 1.6% for women. Elevated alkaline phosphatase (ALP) levels in asymptomatic patients have an age-adjusted incidence of 12.7 and 7 per 100,000 person-years in men and women, respectively.
The etiology of Paget's disease of bone remains unknown, but evidence supports both genetic and viral etiologies. A positive family history is found in 15–25% of patients and, when present, raises the prevalence of the disease seven- to tenfold among first-degree relatives.
A clear genetic basis has been established for several rare familial bone disorders that clinically and radiographically resemble Paget's disease but have more severe presentation and earlier onset. A homozygous deletion of the TNFRSF11B gene, which encodes osteoprotegrin (Fig. 355-1), causes juvenile Paget's disease, also known as familial idiopathic hypophosphatasia, a disorder characterized by uncontrolled osteoclastic differentiation and resorption. Familial patterns of disease in several large kindred are consistent with an autosomal-dominant pattern of inheritance with variable penetrance. Familial expansile osteolysis, expansile skeletal hyperphosphatasia, and early-onset Paget's disease are associated with mutations in TNFRSF11A gene, which encodes RANK (receptor activator of nuclear factor-κB), a member of the tumor-necrosis factor superfamily critical for osteoclast differentiation (Fig. 355-1). Finally, mutations in the gene for valosin-containing protein cause a rare syndrome with autosomal-dominant inheritance and variable penetrance known as inclusion body myopathy with Paget's disease and frontotemporal dementia (IBMPFD). The role of genetic factors is less clear in the more common form of late-onset Paget's disease. Although a few families with mutations in the gene encoding RANK have been reported, the most common mutations identified in familial and sporadic cases of Paget's disease have been in the SQSTM1 gene (sequestasome-1 or p62 protein) in the C-terminal ubiquitin-binding domain. The p62 protein is involved in NF–κB signaling and regulates osteoclastic differentiation. The phenotypic variability in patients with SQSTM1 mutations suggests that additional factors, such as other genetic influences or viral infection, may influence clinical expression of the disease.
Diagram illustrating factors that promote differentiation and function of osteoclasts and osteoblasts and the role of the RANK pathway. Stromal bone marrow (mesenchymal) cells and differentiated osteoblasts produce multiple growth factors and cytokines, including macrophage colony-stimulating factor (M-CSF), to modulate osteoclastogenesis. RANKL (receptor activator of NFκB ligand) is produced by osteoblast progenitors and mature osteoblasts and can bind to a soluble decoy receptor known as OPG (osteoprotegerin) to inhibit RANKL action. Alternatively, a cell-cell interaction between osteoblast and osteoclast progenitors allows RANKL to bind to its membrane-bound receptor, RANK, thereby stimulating osteoclast differentiation and function. RANK binds intracellular proteins called TRAFs (tumor necrosis factor receptor–associated factors) that mediate receptor signaling through transcription factors such as NFκB. M-CSF binds to its receptor, c-fms, which is the cellular homologue of the fms oncogene. See text for the potential role of these pathways in disorders of osteoclast function such as Paget's disease and osteopetrosis.
Several lines of evidence suggest that a viral infection may contribute to the clinical manifestations of Paget disease, including (1) the presence of cytoplasmic and nuclear inclusions resembling paramyxoviruses (measles and respiratory syncytial virus) in pagetic osteoclasts and (2) viral mRNA in precursor and mature osteoclasts. The viral etiology is further supported by conversion of osteoclast precursors to pagetic-like osteoclasts by vectors containing the measles virus nucleocapsid or matrix genes. However, the viral etiology has been questioned by the inability to culture a live virus from pagetic bone and by failure to clone the full-length viral genes from material obtained from patients with Paget's disease.
The principal abnormality in Paget's disease is the increased number and activity of osteoclasts. Pagetic osteoclasts are large, increased 10- to 100-fold in number and have a greater number of nuclei (as many as 100 compared to 3–5 nuclei in the normal osteoclast). The overactive osteoclasts may create a sevenfold increase in resorptive surfaces and an erosion rate of 9 μg/day (normal is 1 μg/day). Several causes for the increased number and activity of pagetic osteoclasts have been identified: (1) osteoclastic precursors are hypersensitive to 1,25(OH)2D3; (2) osteoclasts are hyperresponsive to RANK ligand (RANKL), the osteoclast stimulatory factor that mediates the effects of most osteotropic factors on osteoclast formation; (3) marrow stromal cells from pagetic lesions have increased RANKL expression; (4) osteoclast precursor recruitment is increased by interleukin (IL) 6, which is increased in the blood ...