A pagetic elderly lady with back pain.

An elderly lady suffering from Paget's disease presented with severe back pain after sustaining a fall. The rise in inflammatory markers and poor response to analgesics led to the diagnosis of septic discitis [corrected] that was confirmed by MRI. A high index of suspicion for septic discitis [corrected] is necessary in elderly patients presenting with back pain and an associated rise in inflammatory markers.

Mouth bacteria as the cause of Paget's disease of bone.

The many viruses associated with Pagetic osteoclasts could be opportunistic rather than causative. Some mouth bacteria can lyse bone. One (Actinobacillus actinomycetemcomitans) can grow and even multiply inside human cell lines in culture, producing osteolytic materials -- one 62 kDa protein having a potency in the picomolar range. A small focus of this, or of one of the other periodontitis-causing bacteria, in a bone might gradually spread its influence to activate osteoclasts -- the first stage in Paget's disease. The focus in each bone might be small and easily overlooked, as other intracellular bacteria have been in the past.

Absence of paramyxovirus RNA in cultures of pagetic bone cells and in pagetic bone.

It has been proposed that Paget's disease of bone is caused by the infection of bone cells with one or several paramyxoviruses. In this study we used the polymerase chain reaction (PCR), which allows the detection of very low levels of a target nucleic acid sequence, to study cultures of pagetic bone cells and samples of pagetic bone. Oligonucleotide primers were designed to flank a sequence of the nucleocapsid genome of measles virus and canine distemper virus (CDV). Within this fragment there were contrasting restriction endonuclease sites specific to measles or CDV that allowed identification of the original template. We were unable to detect paramyxovirus RNA in four strains of human bone cells outgrown from pagetic bone and one strain derived from an uninvolved site of a patient with Paget's disease. Furthermore, paramyxovirus sequences were not detected in cDNA prepared from six samples of pagetic bone biopsies. The work presented here further questions the role of measles and CDV in the abnormal remodeling observed in Paget's disease.

Paget's disease of bone: current concepts in pathogenesis and treatment.

Recent advances have been made in understanding the aetiology, diagnosis and treatment of Paget's disease of bone (osteitis deformans). The role of viruses in the pathogenesis of the disease has been extensively investigated, although no causative link has yet been demonstrated between infective agents and Paget's disease. Recent advances in the diagnosis of the disease have been made with increasing usage of radionucleotide imaging to determine the extent and distribution of the lesions. Treatment options have been extended with the emergence of the biphosphonates as potential main line therapeutic agents.

Dogs, distemper and Paget's disease.

The cause of Paget's disease is still unknown, despite many years of intensive study. During this time, evidence has sporadically emerged to suggest that the disease may result from a slow viral infection by one or more of the Paramyxoviruses. More recently, epidemiologic and molecular studies have suggested that the canine paramyxovirus, canine distemper virus, is the virus responsible for the disease. If true, then along with rabies, this would be a further example of a canine virus causing human disease. Studies in the natural host have now supported these findings. Further investigations have proposed that the bony abnormalities seen in Paget's disease are due to the effects of the virus on osteoclastic interleukin-6 and c-FOS production, possibly via the transcription factor NF-kappa B.

Prevalence of canine distemper antibodies in the pagetic population.

Recent molecular evidence has implicated canine distemper virus (CDV) as a possible aetiologic agent in Paget's disease. However, previous serological studies have shown no differences in levels of anti-CDV antibodies between Paget's patients and controls. In this study, the technique of enzyme linked immunosorbent assay was used to measure anti-CDV antibodies in a group of Paget's patients from the North West of England. Some patients were undergoing treatment with 3-amino-hydroxypropylidene (APD), and the pre-treatment levels of antibody were compared with those following treatment. With several patients, it was also possible to compare the antibody levels with results from in situ hybridisation studies. No significant difference was found between the levels of anti-CDV antibodies in patients and controls. However, several patients and some of the controls did have markedly elevated levels of anti-CDV antibody. Antibody levels remained fairly constant following treatment with APD, except for two patients who showed marked changes. The patients positive for CDV by in situ hybridisation had significantly lower levels of anti-CDV antibodies when compared with those that were negative by in situ hybridisation. These results suggest that if CDV does cause Paget's disease, anti-CDV antibodies play little or no part in the disease pathogenesis. High levels of anti-CDV antibodies in both Paget's patients and controls suggest that a canine virus can infect humans. The fact that those patients that had CDV transcripts detectable in their bone cells had low levels of anti-CDV antibodies might suggest failure to clear the virus during an initial infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Paramyxoviruses and Paget's disease.

Using the technique of in situ hybridisation, we extended our initial studies of the occurrence of canine distemper and measles virus in Paget's disease. Bone samples from untreated patients and patients treated with 3-amino-hydroxypropylidene 1,1 bisphosphonate pamidronate (APD) were examined for canine distemper nucleocapsid (CDV-N), measles nucleocapsid (MV-N), respiratory syncytial virus fusion (RSV-F), and simian virus 5 haemoglutinin-neuraminidase (SV5-HN) sequences using 35S-labelled sense and antisense riboprobes. Only CDV-N mRNA was detected in osteoclasts, osteoblasts, and mononuclear cells. In untreated Paget's patients, 63.5% were found to have CDV sequences residing in bone cells, and 48.2% of those undergoing APD treatment were still found to have the viral sequences. RSV-F mRNA was only found in one patient. None of the other paramyxoviruses tested were detected. This study shows that CDV can infect a human host and may be an aetiological agent of Paget's disease of bone.

Canine distemper virus transcripts detected in the bone cells of dogs with metaphyseal osteopathy.

Using the technique of in situ hybridisation, we have recently extended our observations that canine distemper virus (CDV) is present in the bone cells of patients with Paget's disease, and have shown that CDV is also detectable in the bone cells of dogs that are naturally infected with the virus. Since hybridisation was localised to bone cells within the metaphyses of the affected dogs, we investigated the possibility that CDV might be involved in the canine metaphyseal bone disorder, metaphyseal osteopathy. Bone samples from three cases of metaphyseal osteopathy were examined for the presence of the CDV nucleocapsid (CDV-N) gene and the measles virus nucleocapsid (MV-N) gene, using 35S-labelled sense and antisense riboprobes. As with our previous findings in Paget's disease of bone, only the antisense probe was found to hybridize to the osteoblasts and osteoclasts within the affected metaphyses. No hybridisation was seen with the CDV-N sense and MV-N probes in any of the samples tested. Bone samples were also taken from one of the cases to check for the presence of the CDV-N gene using the polymerase chain reaction (PCR). Our findings with in situ hybridisation were confirmed by PCR and subsequent Southern blotting and probing with a 32P-labelled cDNA probe. The detection of CDV RNA within the bone cells of dogs with metaphyseal osteopathy suggests that this virus may be a cause of the disease and provides further, indirect evidence that CDV might be responsible for the bony abnormalities seen in Paget's disease of bone.

In situ analysis of Paget's disease of bone for measles-specific PCR-amplified cDNA.

Paget's disease of bone is a disease of unknown etiology. The demonstration of viral-like particles on ultrastructural examination and the putative detection of viral antibodies and nucleic acids in the tissues suggest a possible viral association. The purpose of this study was to search for nucleic acid sequences homologous to measles virus using the recently described reverse transcriptase (RT) polymerase chain reaction (PCR) in situ hybridization (ISH) technique. After performing RT PCR ISH utilizing primers specific for the nucleocapsid region of the measles virus, an intense signal was evident in most measles-infected HeLa cells compared with a weak signal in few of these cells using standard cDNA-RNA ISH analysis. Amplified measles nucleic acid was detected in tissue from a patient who died of measles infection and was not detected in any of the 11 cases of Paget's disease of bone studied or in a giant cell tumor of bone that had tubuloreticular inclusions on electron microscopy. Therefore, these data suggest that infection by the measles virus is not associated with Paget's disease of bone.

Canine distemper virus transcripts sequenced from pagetic bone.

Paget's disease is a chronic disease of the skeleton which is believed to be caused by a persistent virus of the paramyxovirus family. There is still conflict as to the precise identity of the virus(es) involved in causing this disease. Our previous results using in situ hybridisation have implicated distemper as a possible cause of this disease. In order to confirm these results, we have reverse transcribed RNA from pagetic bone and have specifically amplified for distemper and measles sequences using the polymerase chain reaction (PCR) technique. We have found that 8/13 of the patients examined had distemper and 1/10 cases had measles nucleic acids sequestered within their bone cells. One individual was found to have both viruses sequestered in his bone cells. Dideoxy sequencing of the distemper virus PCR products revealed 2% base pair changes in the nucleic acid sequences relative to the Onderstpoort strain of canine distemper. We can conclude that in Paget's disease, canine distemper and possible other paramyxoviruses reside in bone cells and that the persistent nature of the virus may be due to mutations in the viral genome.

Failure to detect paramyxovirus sequences in Paget's disease of bone using the polymerase chain reaction.

It is widely believed that Paget's disease of bone is due to a "slow virus" infection of osteoclasts with one of the paramyxovirus group. Controversy continues to surround the identity of the virus involved, however, since at different times evidence has been presented implicating measles virus (MV), respiratory syncytial virus (RSV), and canine distemper virus (CDV) as putative infective agents. In this study we used the technique of reverse transcription and polymerase chain reaction (PCR) to screen for paramyxovirus sequences in ribonucleic acid (RNA) extracted from pagetic bone. We were able to detect viral amplification products of the appropriate size in RNA extracted from as few as 50 cells experimentally infected with a wide range of paramyxoviruses, including measles, canine distemper, parainfluenza 3, and respiratory syncytial virus, but we found no evidence of viral products in RNA extracts of affected bone from 10 consecutive patients with Paget's disease. This study fails to support the hypothesis that active infection with one of these or a related paramyxovirus is involved in the pathogenesis of Paget's disease.

Canine distemper virus localised in bone cells of patients with Paget's disease.

The technique of in situ hybridisation was applied using radioactively labelled riboprobes to examine for the presence of canine distemper (CDV) and measles (MV) RNA in Paget's disease of bone. The results indicate that in 41% of Paget's patients, CDV RNA could be detected in osteoclasts, osteoblasts, and osteocytes, but not in controls. In contrast, RNA to the measles virus was not detected. We suggest that CDV may in some cases play a role in the aetiology of Paget's disease.

Dogs, distemper and osteitis deformans: a further epidemiological study.

There is extensive evidence linking paramyxoviruses, notably measles and respiratory syncytial virus, with Paget's disease of bone. The epidemiology of Paget's disease does not fit with that of known human paramyxovirus infections and it is possible that the disease is a zoonosis with domestic animals acting as host. Canine distemper, a paramyxovirus of the morbillovirus family (closely related to measles) is therefore a potential candidate. We have surveyed previous pet ownership in 150 Paget's patients each of whom was matched with two general practice controls; one from an inner city practice and the other from a suburban practice both in Greater Manchester. Recall of previous dog ownership was higher in Paget's patients with differences being more marked against inner city than suburban controls. 88% of the patients had lived in the same household as a dog at some stage compared with 79% of the inner city controls (P less than 0.05) and 83% of the suburban controls (n.s.). The differences were greater in the years 1930-60 during which the proportion of patients owning dogs was largest. For Paget's patients and controls alike, recalled exposure to dogs with canine distemper appeared to cluster in certain periods between 1930 and 1960. Unexpectedly, significantly more (7 out of 22, P less than 0.01) of the patients with a known first degree relative suffering from Paget's disease had no previous history of dog ownership when compared with the other patients (10 out of 128).

Osteoclasts in human osteopetrosis contain viral-nucleocapsid-like nuclear inclusions.

We report the discovery of nuclear inclusions in the osteoclasts of three unrelated patients with benign osteopetrosis that resemble the osteoclast inclusions characteristic of Paget's disease of bone. These inclusions are morphologically and dimensionally identical to the nucleocapsids of a virus of the Paramyxoviridae family. Supporting a possible viral association with benign osteopetrosis in the observation of the presence of antigens of respiratory syncytial virus, measles virus, and/or mumps virus in the cells of all five patients whose paraffin-embedded bone specimens were tested. These included two patients whose osteoclasts contained nuclear inclusions. No patients with the malignant form of the disease have been studied. There is as yet no proof that a virus is causally related to human osteopetrosis even though a virus can produce an avian form of the disease.