Paget's disease of bone

Paget's disease of bone is defined as a process of increased bone remodeling; the primary event is increased resorption (osteoclastic activity) followed by subsequent reactive bone formation (osteoblastic activity). It is usually asymmetric and may be asymptomatic. The etiology is unknown, but recent evidence appears to support the theory that a virus is an important etiologic factor. It may present with a wide variation in the clinical and radiographic picture. The most frequent sites of involvement include the spine, femora, cranium, pelvis, and sternum. The most common complaints are pain, skeletal deformity, and change in skin temperature. Pathologic fractures may be the presenting manifestations or complications in a patient with known Paget's disease. They occur most frequently in the long weight-bearing bones of the lower extremities such as the femoral neck and subtrochanteric and tibial regions. The two major therapeutic agents available for treatment are calcitonins (porcine, salmon, or human) and diphosphonates. The aim of such therapy is to control the metabolic activity of the disease, to normalize the biochemical parameters, and to improve the symptoms. Fortunately, tumors are rare; early diagnosis may give rise to more effective palliation, if not a significant cure rate.     

Genetics of Paget's disease of bone

Paget's disease of bone is a chronic bone disease that affects up to 3% of Caucasians older than 55 years. The cause of Paget's disease is unknown but involves genetic factors. Familial cases display an autosomal dominant pattern of inheritance with incomplete penetrance. Genetic heterogeneity has been demonstrated and eight potential susceptibility loci identified. There is sound evidence incriminating Sequestosome 1 (SQSTM1) on the long arm of chromosome 5 (5q35-qter), of which nine mutations have been described in Paget's disease of bone. These mutations are located in exons 7 and 8, which encode a highly conserved ubiquitin-binding domain. The prevalence of SQSTM1 mutations is about 10% in France. Tests for SQSTM1 mutations should be done in patients with Paget's disease of bone, even where the family history is negative. Detection of a mutation allows evaluation of family members to ensure early diagnosis of the disease before complications develop.     

Treatment of Paget's disease of bone

This report presents clinical pictures of 11 patients with Paget's disease of bone treated at our clinic since 1977 and discusses the disease progress in seven patients who were given Elcatonin and EHDP and followed-up for a mean period of four years and eight months. All the patients responded to the drugs and the main clinical effect was disappearance of pain. They did not develop side effects which were especially a problem. Although both of the drugs exerted excellent effect on Paget's disease of bone, they have both strong and weak points with respect to administration route and side effects. These drugs should be selected with combined therapy, clinical effectiveness, side effects and other factors taken into account. Bone scintigram, serum alkaline phosphatase and urinary hydroxyproline were employed as therapeutic effect of these drugs. However, their handiness and reliability were unsatisfactory. More convenient parameters reflecting the disease activity more accurately are needed.     

Atypical familial Paget's disease of bone

We report unusual clinical and radiological features of Paget's disease of bone in three family members. All three patients had satisfactory biochemical and symptomatic response to treatment with an intravenous bisphosphonate (clodronate).     

Current concepts of Paget's disease of bone

Paget's disease of bone is a process of increased bone remodeling resulting in architecturally abnormal bone that may affect any area of the skeleton. Paget's disease may present with a wide variation in the clinical and radiographic picture. When symptoms arise, they depend on the site and the extent of skeletal involvement. The two major therapeutic agents available for medical treatment are calcitonin and diphosphonate. Surgical intervention in Paget's disease is indicated for (1) selected fractures, (2) severe disabling arthritis, and (3) extreme bowing deformities causing malalignment of weight-bearing joints.     

Familial aggregation of Paget's disease of bone

This epidemiologic study of Paget's disease of bone used data from 788 cases and 387 spouse controls to investigate the following: (1) the extent to which this disorder aggregates in families; (2) the cumulative incidence of the disease in first-degree relatives of patients throughout life; and (3) the influence of age at diagnosis (less than 55 versus 55+ years) and presence of bone deformity in the case on risk of Paget's disease in relatives. A positive family history in parents or siblings was reported by 12.3% of cases and 2.1% of controls. The rate of Paget's disease was approximately seven times as high in relatives of cases as in relatives of controls, and this increased rate did not differ according to gender of case or control or gender of relatives. Cumulative incidence of Paget's disease to age 90 was much higher in relatives of cases (8.9 +/- 1.0% SEM) than in relatives of controls (1.8 +/- 0.9% SEM). Among relatives of cases, cumulative risk was highest when the case had both early age at diagnosis and bone deformity (20.7 +/- 3.6% SEM) compared with risk when the case had early age at diagnosis but not bone deformity (10.8 +/- 3.2% SEM), bone deformity but not early age at diagnosis (5.8 +/- 1.3% SEM), or neither bone deformity nor early age at diagnosis (3.6 +/- 0.8% SEM). Risk in siblings of cases was higher when a parent was affected (22.1 +/- 8.0% SEM) than when both parents were unaffected (6.7 +/- 1.1% SEM).(ABSTRACT TRUNCATED AT 250 WORDS)     

Gene-environment interactions in Paget's disease of bone

ObjectivesThis study explored the role of outdoor and indoor air pollutants in Paget's disease of bone (PDB).MethodsWe performed a survey in 140 French-Canadian patients with PDB, including 39 carriers of p.Pro392Leu mutation (SQSTM1 gene) and 113 healthy not mutated controls. The survey covered outdoor air pollution near the residence and indoor air pollutants by focusing on heating fuels and exposure to tobacco smoke. In a subgroup of patients, urinary concentrations of 17 heavy metals and 11 polycyclic aromatic hydrocarbons were measured by mass spectrometry. In light of what we learned from the survey and urinary assays, we explored the in vitro effects of certain toxics on osteoclasts in PDB. We conducted in vitro monocytes differentiation from peripheral blood of more than 40 participants, whose osteoclasts were treated with or without the toxic. The morphology of osteoclasts, their bone resorption abilities, gene and protein expression levels, and cellular oxidative stress levels were assayed.ResultsAn inhibitory effect of cigarette smoke condensate and heavy metals was observed on morphology and bone resorption activity of patients’ osteoclasts. SQSTM1 gene expression was upregulated in osteoclasts from patients with PDB versus healthy controls in presence of cadmium, and SQSTM1 protein expression was upregulated in presence of bismuth and tobacco smoke condensates, in particular in osteoclasts from carriers of the SQSTM1 mutation. Furthermore, high levels of oxidative stress in patients’ osteoclasts were observed.ConclusionsOur in vitro experiments suggest an interaction between SQSTM1 gene and exposure to cadmium and tobacco smoke condensates.     

HLA-D antigens and Paget's disease of bone

HLA-A, -B, -C, -DR, and -DQ antigens were determined in 25 Ashkenazi Jews with Paget's disease of bone. HLA-DR2 was more frequent in the Pagetic patients compared with 57 healthy controls of the same ethnic origin. This finding concurs with a previous report and raises the possibility that HLA-DR2 may be associated with Paget's disease of bone, probably by predisposing the bone cells to viral infection.     

Robertsonian translocations in Paget's disease of bone

The karyotypes of 14 patients with Paget's disease of bone were studied. The patients were recruited from our bone metabolism clinic where they received specific therapy for their skeletal disease. Eight of the 14 patients had chromosomal translocations localized to the D and G groups. None of the patients were related to one another, nor had any had the same lifelong environment. Thus, 57% of a sample of active patients with Paget's disease had Robertsonian translocations. By comparison, an age and sex-matched group of eight controls and 13 patients with osteoporosis who had been treated with bisphosphonates demonstrated no Robertsonian translocations. The prevalence of Robertsonian translocations in 14,000 newborns was reported to be 0.1%. These data suggest that a factor from the environment introduced during the lifetime of the patient could be present and could, in addition to genetic factors, affect gene replication during the development of Paget's disease.     

佩吉特骨病1例

<正>患者女,63岁,因"无诱因出现间断性头痛5年余,近1个月加重,咳嗽时双颞侧剧烈跳痛"就诊。查体:头部及四肢关节未见畸形、活动障碍等异常。实验室检查:碱性磷酸酶(alkaline phosphatase, ALP)1 668 U/L。骨密度检测提示骨量减少。头颅X线片:颅骨轮廓尚见,头皮软组织肿胀,骨质内多发混杂密度影,病灶形状不规则;提示颅骨多发病变。胸部、双侧肱骨、骨盆X线检查骨质均未见明显异常。全身骨显像:颅骨弥漫性摄取增强,放射性