Paget’s disease of bone (PDB) is a common metabolic disorder, presumably triggered by both genetic and environmental factors. Many patients have a positive family history of PDB, an observation that has led to the hypothesis of there being a familial form of the disease. It is usually inherited in an autosomal dominant manner with incomplete penetrance. Still, whether there is a true familial form of PDB or whether PDB is a multifactorial disease whose onset is favored by a certain genetic predisposition, remains to be clarified.
The majority of patients remains clinically asymptomatic. Only about 5% of PDB patients suffer from dull, deep and predominantly nocturnal bone pain and arthralgia secondary to osteoarthritis . Skeletal deformities become apparent years after disease onset and may include growth deficiencies in patients suffering from early-onset PDB. In both minors and adults, any bone of the axial or appendicular skeleton may be affected, but deformities most commonly emerge in weight-bearing areas  . While sporadic PDB is often limited to one or two bones, a mean of four bones is affected in patients suffering from the familial form of the disease  .
Additional symptoms of PDB comprise premature loss of dentition as well as headaches and neurological deficits, particularly deafness, due to hyperostosis of the skull and compression of nerves . As for familial PDB, there is considerable heterogeneity in age of symptom onset and disease severity among members of the same family .
Familial clustering has been observed in many cases and is the most important feature to distinguish familial from sporadic PDB . According to retrospective studies, up to 40% of PDB patients have relatives who also suffer from this metabolic disorder  . However, familial PDB is known to have an incomplete penetrance and thus, a negative family history does not rule out familial PDB. The predisposition of an individual patient to PDB may be shown by means of genetic studies, but it should be noted that family members carrying certain mutations don't necessarily develop clinical disease, which is due to the incomplete penetrance that has been mentioned above .
Still, genetic analyses are recommended in the workup of familial PDB since the determination of sequence anomalies in the patient at hand is the prerequisite for targeted analyses in their relatives. Based on the results of such analyses, family members may be assigned a certain PDB risk score . Once individuals at risk have been identified, they may be referred for regular prophylactic screenings. Radiography and bone scintigraphy are the most important tools to diagnose PDB and may be employed in such screenings . In affected bones, foci of lytic and sclerotic lesions, hyperostosis and deformities can be observed . Repeated episodes of osteolysis followed by disorganized skeletal repair eventually yield a mosaic-like appearance of affected bones . If bone tissue is obtained by means of biopsy, histological examinations may be carried out and typically reveal focal lesions of increased bone resorption and formation of woven bone . Bone biopsies are rarely necessary to confirm the diagnosis of PDB, but they provide valuable information on a possible neoplastic transformation .
Alternatively, biochemical testing may be conducted during prophylactic examinations or for unrelated reasons. Abnormal findings in blood sample analyses may suggest a bone disorder and may prompt imaging studies as described above. In case of PDB, increased serum alkaline phosphatase levels and hypercalcemia may be ascertained, whereby the latter is not a constant feature but only present during periods of immobilization. Serum concentrations of alkaline phosphatase also serve as a marker of PDB activity and are usually assessed in follow-ups .
Therapy of familial PDB doesn't differ from that of sporadic PDB and mainly relies on the application of bisphosphonates. Zoledronic acid is the most potent active compound, is least likely to induce resistance and is thus the drug of choice . Calcitonin may also be administered: It is used to reduce osteoclast activity and to manage PDB-associated bone pain . Pharmacotherapy isn't usually initiated before the onset of clinical symptoms, but prophylactic bisphosphonate therapy has been recommended for patients with asymptomatic high-risk lesions present in skull or spine .
PDB patients are at increased risks of fracture, osteosarcoma and giant cell tumors. While structural anomalies are known to alter the mechanical properties of the bone and predispose to pathological fractures, the triggers of neoplastic degeneration of PDB lesions have not yet been identified. Malignant transformation significantly worsens the patients' prognosis, but fortunately, it is rarely observed. In most cases, long-term remission can be achieved by treatment with potent bisphosphonates. While imaging studies will continue to show certain anomalies of bone structure, lytic lesions are usually healing during therapy .
The etiology of PDB remains incompletely understood, but genetic factors seem to play a key role in the development of the disease. Indeed, it has been hypothesized that familial PDB is inherited in a mainly autosomal dominant manner with incomplete penetrance . Several genes involved in osteoclast differentiation, maturation, or function have been associated with PDB:
Of note, similar mutations have also been identified in patients with apparently sporadic disease . For instance, SQSTM1 mutations are identified in 10% of patients suffering from sporadic PDB .
Additionally, distinct environmental factors have been discussed with regards to their role in PDB etiology. In this context, viral pathogens like measles virus have attracted considerable attention and mass vaccinations against measles have been speculated to account for the decreasing incidence of PDB . On the other hand, increments in circulating parathyroid hormone levels have been proposed to trigger the disease. However, it remains a matter of ongoing debate whether PDB is associated with primary or secondary hyperparathyroidism . Arsenic and lead exposure may also favor the onset of PDB .
PDB is a very common metabolic disorder, affecting up to 3% of the population aged >40 years in Europe and North America. For people aged >55 years and >80 years, the prevalence of PDB augments to 5 and 8-10%, respectively  . For PDB, the mean age at symptom onset is 55 years, but familial PDB tends to manifest in the fifth decade of life . Though PDB is rarely diagnosed in individuals younger than 40 years, early-onset forms of the disease have been described  . Interestingly, the overall prevalence of PDB seems to be declining - an observation that may support the hypothesis of measles virus playing a role in PDB etiology . It has also been argued that rural residency, wood fired heating, and contact with farm animals may favor the onset of the disease, and that rural-urban migration accounts for the decreasing prevalence of PDB . Interestingly, disease prevalence remains high in rural regions .
In general, the individual risk of developing PDB is increasing with age. While both men and women may be affected by PDB, male predominance has been reported for subgroups of patients with a positive family history of PDB . With regard to the geographical distribution of PDB, the disease is common in Western and Central Europe, North America, Australia, and New Zealand, but it is rare in Scandinavia and Asia .
In patients suffering from familial PDB, the pathogenetic events leading to dysregulated osteoclast and osteoblast are triggered by distinct germline mutations and environmental factors as described above: Findings typical of early PDB comprise focal lytic lesions in one or multiple bones. Histological studies have shown that the absolute number of osteoclasts is increased in these lesions, and that osteoclasts of PDB patients are larger and contain more nuclei than normal osteoclasts. There may be nuclear and cytoplasmic inclusion bodies. The development of osteoclast-induced lytic lesions is followed by a proliferation of osteoblasts. Due to enhanced osteoblast activity, lytic lesions evolve into sclerotic ones within years after disease onset. At the same time, hematopoietic bone marrow is replaced by fibrovascular marrow rich in precursors of osteoclasts and osteoblasts .
If familial PDB can be related to a specific mutation in a determined family, this family might benefit from genetic counseling. In this case, early, even prenatal risk assessment would become feasible. High-risk family members might then be recommended for regular imaging studies to facilitate the early detection of structural anomalies of the bone. However, it has not yet been clarified whether treatment before symptomatic disease is beneficial for the patient.
PDB is the second most common metabolic bone disorder, second only to osteoporosis. PDB is also referred to as osteitis deformans and is caused by dysfunctional remodeling of the bone, excessive degradation and abnormal generation of osseous tissues. Although the etiology of the disease remains incompletely understood, genetic factors are known to play key roles in it. In general, causal mutations may be inherited or acquired, but familial clustering is often observed and argues for PDB to be a hereditary disorder. It has been shown that first-degree relatives of PDB patients have a 7-fold increased risk of developing PDB than those with a negative family history . In this context, familial PDB may be distinguished from sporadic PDB. It has been estimated that about one third of PDB patients suffers from familial PDB .
Paget’s disease of bone (PDB) is a common metabolic bone disorder. It is usually diagnosed in patients aged >40 years and follows a slowly progressive course if left untreated. According to current knowledge, both genetic and environmental factors contribute to the onset of PDB. Familial clustering is frequently observed and argues for a key role of inherited traits in PDB pathogenesis. Indeed, first-degree relatives of PDB patients have been shown to have a 7-fold increased risk of developing the disease than those with a negative family history. Therefore, the term familial PDB has been coined.
Clinical presentation and therapy of familial PDB don't differ from those of the sporadic disease. Most patients remain asymptomatic for prolonged periods of time; few suffer from bone pain, joint pain secondary to osteoarthritis, fractures due to bone instability, or skeletal deformities. Any bone may be affected, but the disease is usually limited to about four bones in the whole body. The disease is diagnosed by means of blood sample analysis and diagnostic imaging. In fact, such studies may be realized for unrelated reasons and may suggest PDB in asymptomatic patients. In case of familial PDB, genetic studies may be carried out to determine the underlying mutation and to conduct targeted analyses in family members. This way, family members at risk can be identified and referred to regular prophylactic screenings.