Key points

Introduction

Paget disease was first described in 1877 by Sir James Paget, a physician at St Bartholomew’s Hospital in London, England. Sir Paget described a series of middle-aged patients who presented with aberrant bony structure. As he followed these patients, he went on to notice progressively worsening bony deformities at multiple sites of involvement. Some of his patients went on to develop bone sarcomas that ultimately led to their demise. Over the last 137 years, how much has our understanding of this disease evolved? Are we, as clinicians, better adept in the screening, earlier identification, assessment, and treatment of this disease?

This review aims to provide a synopsis of our current understanding and discusses the progress made, the controversies, and the current medical and surgical principles of treatment. We now know this condition is the result of disordered bone remodeling, as opposed to James Paget’s initial perception of this being an osteitis or inflammation of the bone. This disease results from an uncoupling of the normal equilibrium of bone formation and resorption. Subsequently, the normal architecture of the affected bone is replaced by disorganized bony tissue that is structurally weaker and is, over time, subject to stress deformities and pathologic fractures. In the long-term, a subset of patients with Paget disease of bone (PDB) will undergo malignant transformation, developing Paget sarcoma, a biologically malignant neoplasia, usually an osteosarcoma, with a poor prognosis.

Introduction

Paget disease was first described in 1877 by Sir James Paget, a physician at St Bartholomew’s Hospital in London, England. Sir Paget described a series of middle-aged patients who presented with aberrant bony structure. As he followed these patients, he went on to notice progressively worsening bony deformities at multiple sites of involvement. Some of his patients went on to develop bone sarcomas that ultimately led to their demise. Over the last 137 years, how much has our understanding of this disease evolved? Are we, as clinicians, better adept in the screening, earlier identification, assessment, and treatment of this disease?

This review aims to provide a synopsis of our current understanding and discusses the progress made, the controversies, and the current medical and surgical principles of treatment. We now know this condition is the result of disordered bone remodeling, as opposed to James Paget’s initial perception of this being an osteitis or inflammation of the bone. This disease results from an uncoupling of the normal equilibrium of bone formation and resorption. Subsequently, the normal architecture of the affected bone is replaced by disorganized bony tissue that is structurally weaker and is, over time, subject to stress deformities and pathologic fractures. In the long-term, a subset of patients with Paget disease of bone (PDB) will undergo malignant transformation, developing Paget sarcoma, a biologically malignant neoplasia, usually an osteosarcoma, with a poor prognosis.

Natural history and epidemiology

Anthropological analyses of skeletal remains indicate that PDB first appeared in Western European populations during the Roman period. Multiple prevalence surveys carried out since the 1970s have demonstrated that PDB becomes more prevalent with increased age and that men are more frequently affected when compared with women. Additionally, geographic differences also exist, with PDB being more common in the United Kingdom and other Western European nations and less prevalent in Scandinavia, Eastern Europe, and Asia. Follow-up prevalence studies have revealed a gradual decline in prevalence of PDB since the 1970s, with some studies indicating rates almost 50% less. PDB typically presents in middle-aged and older populations. It can arise as a monostotic or polyostotic disease, with more recent epidemiologic studies favoring the monostotic variety as being more common. The pagetic lesion typically expands in size without treatment, and serial radiographs often demonstrate marginal expansion in size (approximately 0.8 cm per year) in the setting of a radiographic evidence of lysis and sclerosis, concurring with the microscopic findings of increased bone turnover (both bone resorption and bone formation).

Cause and genetics

Both genetic and environmental factors have been implicated in the development of PDB. Historical review of patients and families with PDB has revealed both familial and sporadic subtypes. Hocking and colleagues and Laurin and colleagues first posited in 2002 that the familial subtype of PDB was strongly associated with mutations in the sequestosome 1 or p62 gene, SQSTM1. This gene encodes a ubiquitously expressed protein found in the nucleus and cytoplasm of most cells and has been associated with multiple cellular activities, including nuclear factor kappa B signaling, modulation of potassium channels, control of transcription, autophagy, and sequestration and subsequent degradation of ubiquinated proteins. In bone specifically, it is still unclear as to the inhibition of which of these activities results in the metabolic derangements manifested in the phenotype of PDB.

SQSTM1 mutations were noted in approximately 20% to 40% of familial PDB and up to 5% of sporadic cases of PDB. In a follow-up study in 2004, Hocking and colleagues reported that patients with SQSTM1 mutations experience more severe phenotypes of PDB, including evidence of earlier onset and manifestations of disease at multiple skeletal sites.

Penetrance studies of SQSTM1 mutations, however, imply that the genetic mutation alone is not necessarily responsible for manifestation of PDB. Although penetrance of SQSTM1 mutations was originally estimated to be greater than 80% at 70 years of age in observational studies in families in which the disease was highly expressed, several studies have failed to find manifestations of PDB in appropriately aged mutation carriers.

In addition to the potential genetic underpinnings of PDB described earlier, an alternative cause has been proposed, a potential infection with paramyxoviruses. This theory stemmed from the observation that paramyxoviral-like nuclear inclusions are commonly present in osteoclasts in pagetic bone. Some studies have reported detection of viral mRNA or protein based on biotechnological amplification methods in samples obtained from patients with PDB and have comparatively failed to find similar mRNA or protein in controls. Yet other studies have also failed to detect viral RNA or protein. Similarly, live para-myxovirus has never been isolated from diseased tissue.

Pathology and pathophysiology

Fundamentally, PDB is characterized by accelerated remodeling of bone. Microscopically, the disease is a mixture of focal areas of excessive bone resorption and areas of abundant new bone formation with replacement of normal bone marrow with vascular and fibrous tissue. The progression of the disease has been categorized into phases based on radiographic and histologic criteria. Early in the disease, excessive bone resorption predominates in focal regions with high concentrations of osteoclasts. These osteoclasts are usually multinucleated and actively resorb bone. After this phase, increased bone formation is noted, with increased concentrations of hyperactive osteoblasts, with bone formation rates increased 6- to 7-fold over the basal steady state. The bone deposition is somewhat disorganized rather than following a smooth, lamellar pattern. As the rapid bone formation phase starts to predominate in more advanced stages of PDB, the lesions become more sclerotic, leading to thickening of bone and subsequent replacement of the bone marrow with vascular and fibrous tissue. The presence of woven bone and marrow fibrosis is also seen in other high bone turnover conditions. As a result, these histologic changes are often considered epiphenomena to an underlying high bone-remodeling rate and not pathognomonic for PDB. Please see Fig. 1 .

( A ) Gross resection specimen of a patient with PDB. The cortex is thickened and bony trabeculae are coarse, irregular, and thickened. ( B ) Histologic specimen demonstrating thickened bony trabeculae with the characteristic mosaic pattern and osteoclastic and osteoblastic activity (hematoxylin-eosin, original magnification ×10).

( Courtesy of Dr G. Petur Nielsen, Massachusetts General Hospital.)

Clinical presentation

Paget disease can often be silent or asymptomatic until secondary abnormalities from progressive disease become apparent. Among the symptomatic group, the most common presentation is poorly localized bone pain. Typically the pain is constant, present at rest, and worst at night. Secondary causes include pathologic stress fractures through abnormally enlarged, weak, and deformed pagetic bone and secondary osteoarthritis in adjacent joints usually resulting from bony deformity and altered biomechanical forces. In the skull, bony enlargement can cause nerve compression leading to deafness; in the spine, bony deformity and exuberant bone growth can cause symptoms related to spinal stenosis and/or radicular compression. Studies have demonstrated that the level of bone pain is directly proportional to the level of disease activity.

Medical management of Paget disease

The principal indications for medical treatment of Paget disease are to relieve symptoms of bone pain and prevent complications arising from unchecked destruction of healthy bone and abnormal overgrowth of pagetic bone. This approach for treatment is particularly applicable to the subset of the Paget population with skull base involvement at risk of deafness or spinal cord compromise caused by bone overgrowth or at risk of fracture caused by the involvement of weight-bearing bones. Other medical indications for treatment include optimization of bone turnover to reduce vascularity in patients undergoing elective surgery, such as joint arthroplasty. In such cases, decreased vascularity of pagetic bone can help reduce intraoperative blood loss. Finally, antiresorptive treatment may also be appropriate in patients with polyostotic Paget disease with hypercalcemia as a means of treating the underlying cause of the electrolyte derangement.

The long-term efficacy of prophylactic treatment of asymptomatic patients with PDB is still not clear. Some investigators report no reduction in complications or clinical benefits in randomized controlled trials comparing asymptomatic patients with PDB receiving bisphosphonate treatment to normalize bone turnover markers versus those patients being treated for symptomatic disease. Other studies report that patients who have undergone long-term treatment with bisphosphonates, for an average of 12 years, whose bone turnover rates had not normalized, had higher complications. Therefore, some investigators advocate that the potential of these antiresorptive medications to reduce disease progression, bone deformity, and related complications is significant enough to treat this asymptomatic subset of patients with antiresorptive treatment. However, sufficient data are still lacking as most studies have a relatively short-term follow-up to realize the true long-term benefits of prophylactic treatment in asymptomatic patients. In symptomatic patients, there exists an established consensus on the choice of medical treatment options, which essentially includes bisphosphonates and calcitonin.