Cross-sectional study of patients with VCP multisystem proteinopathy 1 using dual-energy x-ray absorptiometry.

INTRODUCTION/AIMS: VCP multisystem proteinopathy 1 (MSP1), encompassing inclusion body myopathy (IBM), Paget's disease of bone (PDB) and frontotemporal dementia (FTD) (IBMPFD), features progressive muscle weakness, fatty infiltration, and disorganized bone structure in Pagetic bones. The aim of this study is to utilize dual-energy x-ray absorptiometry (DXA) parameters to examine it as a biomarker of muscle and bone disease in MSP1. METHODS: DXA scans were obtained in 28 patients to assess body composition parameters (bone mineral density [BMD], T-score, total fat, and lean mass) across different groups: total VCP disease (n = 19), including myopathy without Paget's ("myopathy"; n = 12) and myopathy with Paget's ("Paget"; n = 7), and unaffected first-degree relatives serving as controls (n = 6). RESULTS: In the VCP disease group, significant declines in left hip BMD and Z-scores were noted versus the control group (p ≤ .03). The VCP disease group showed decreased whole body lean mass % (p = .04), and increased total body fat % (p = .04) compared to controls. Subgroup comparisons indicated osteopenia in 33.3% and osteoporosis in 8.3% of the myopathy group, with 14.3% exhibiting osteopenia in the Paget group. Moreover, the Paget group displayed higher lumbar L1-L4 T-score values than the myopathy group. DISCUSSION: In MSP1, DXA revealed reduced bone and lean mass, and increased fat mass. These DXA insights could aid in monitoring disease progression of muscle loss and secondary osteopenia/osteoporosis in MSP1, providing value both clinically and in clinical research.

Paget's Disease or Densifying Metastasis: How to Sort It Out.

Although the prevalence of Paget's disease has decreased over the past 20 years, incidental discovery on imaging is not unusual. The challenge is to establish the diagnosis, especially in unusual forms that may be mistaken for metastases. This review describes the typical imaging features of Paget's disease and some rare presentations that may be more difficult to recognize.

Prevalence of Paget's disease of bone: review of consecutive abdominopelvic CT scans and literature.

BACKGROUND: Previous studies suggest an overall decrease of Paget's disease of bone (PDB) prevalence. However, a large number of asymptomatic patients make previously reported prevalence likely underrepresented. PURPOSE: To evaluate the prevalence of PDB in our patient population. MATERIAL AND METHODS: We retrospectively identified 1295 (mean age = 59 years; age range = 18-98 years) consecutive abdominopelvic computed tomography (CT) scans over a 15-day period in 2014. Abdominopelvic CT images were reviewed to assess for the presence of PDB in the lower thoracic spine, lumbar spine, pelvis, or proximal femora. This prevalence was compared with prevalence reported in earlier literature using Fisher's exact test. RESULTS: Of the included patients, 5/1295 (0.39%) patients had imaging findings of PDB on abdominopelvic CT. Those five patients were all aged ≥55 years and had pelvic bone involvement, with one patient having additional involvement of multiple lower thoracic vertebral bodies. In our studied cohort, 812/1295 (62.7%) patients were aged ≥55 years, which corresponds to a prevalence of 0.62% (5/812) of PDB in patients aged ≥55 years. When accounting for fact that bones of the pelvis are involved in 40%-91% of patients with PDB, the prevalence is estimated at 0.43%-0.98% in the total adult population and estimated at 0.68%-1.55% in older adults. The prevalence was greater than two studies before 1960, and less than some studies during 1960-2019. CONCLUSION: We found that the prevalence of PDB on abdominopelvic CTs was 0.39% of all adult patients with an increase after the age of 55 years.

"Do-not-touch" lesions of bone revisited.

Incidental bone lesions are encountered frequently in day-to-day practice. Many of these lesions are indeterminate requiring referral to specialist centres for further characterisation with or without biopsy; however, as biopsy has its own drawbacks, not all lesions can be subjected to biopsy. The primary role of a radiologist in these situations is to characterise these lesions based on their imaging appearances into aggressive lesions requiring biopsy and non-aggressive lesions that do not require a biopsy. The term "do-not-touch lesion" is used to describe a lesion with typical radiographic appearances that can be characterised based on radiographic appearances alone without needing a biopsy. With recent advances in imaging, many incidental lesions can be characterised into do-not-touch lesions based on their imaging appearances alone using a single imaging technique or using a combination of imaging techniques and, less frequently, with the additional help of serological investigations, without the need for biopsy. Hence, the definition of do-not-touch lesions of bone needs a revisit. In this article, we attempt to redefine do-not-touch lesions of bone and propose an imaging-based classification for characterisation of these lesions.

Paget's Disease of the Bone: Patterns of Referral to Secondary Care Following Diagnosis on X-rays.

Paget's disease of bone (PDB) is the second commonest metabolic bone disorder in the UK after osteoporosis and is both underdiagnosed and undertreated. PDB is often found incidentally on plain X-rays. There is effective treatment so identification of affected individuals is important. The aim was to conduct an audit to determine what proportion of individuals with X-ray evidence of PDB were referred to secondary care. A retrospective audit of X-rays reports in men and women over 55 years of age was undertaken over 18 months searching for the key word "Paget's." The images of possible cases were reviewed and the presence of PDB confirmed. The proportion already known to secondary care was determined and those that had had isotope bone scans and treatment. Data recorded included site of lesion, age, gender, level of total alkaline phosphatase (ALP) and complications. A total of 68,873 X-rays were screened and 43 cases found. Pelvic images had the highest proportion of positive findings at 0.2% and 65% of the cases. 74% had not been referred to secondary care. The mean age was 86.7 years (range 65-95) and the ALP was elevated in 65% with a mean of 189u/L (range 47-804u/L). In 33 individuals, PDB had been recorded in the reports of previous X-rays. The rate of referral for specialist care remains low. The prevalence of the condition appears to be falling.

An update on imaging of Paget's sarcoma.

Paget's sarcoma is a rare and particularly aggressive tumour arising within pagetic bone, affecting approximately 1% of patients with Paget's disease during the course of their disease. Most of these tumours are osteosarcomas, but the age profile, skeletal distribution and clinical outcomes differ considerably from conventional osteosarcoma. In this review, we outline the clinical, radiographic/CT, scintigraphic and magnetic resonance imaging features of Paget's sarcoma. We also review the neoplastic and non-neoplastic mimics of Paget's sarcoma that should be considered in the differential diagnosis when encountering an aggressive lesion within pagetic bone.

Bone Mineral Densitometry Reporting: Pearls and Pitfalls.

Dual-energy X-ray absorptiometry (DXA) is the method of choice for assessing bone mineral density (BMD). Unfortunately, the performance and interpretation of DXA can be challenging and errors are common. In fact, it has been reported that up to 90% of BMD reports contain at least 1 error. Errors can be the result of technique or interpretative in nature or both and can result in inappropriate diagnosis and management. In this article, we review the various types of pitfalls frequently encountered by physicians interpreting DXA studies. Being aware of these pitfalls will help readers recognize and avoid them when encountered in clinical practice.

Clinical and radiological outcomes of total hip arthroplasty in patients affected by Paget's disease: a combined registry and single-institution retrospective observational study.

BACKGROUND: Total hip arthroplasty (THA) in patients with Paget's disease can be associated with technical difficulties related to deformities and altered mechanical bone properties, and hypervascularity leads to significative intra-operative bleeding. The purpose of this registry and single-institution study was to investigate overall survival and causes of failure of THA in pagetic patients, together with an analysis of the clinical and radiological complications. MATERIAL AND METHODS: Registry-based survival and complication analysis, type of fixation, intra- and post-operative complications, clinical (pharmacological history, blood transfusions, Harris hip score [HHS]) and radiographic (cup orientation, stem axial alignment, osteolysis around the cup and the stem and heterotopic ossification [HO]) data were reviewed. RESULTS: In total, 66 patients (27 males and 39 females, mean age at surgery 71.1 years for males and 74.8 years for female) from the registry study presented a 10-year survival of 89.5%. In the institutional study, involving 26 patients (14 males and 12 females, 69 years average) and 29 THAs, hip function improved significantly. Average cup orientation was 40.5°, while varus stem alignment was 13.8%. In total, 52% of hips had heterotopic ossifications. Peri-acetabular osteolysis was in 13.8% of implants and in 45% of hips was found around the stem. Allogenic and autologous blood transfusion rate were 68.2% and 31.8%, respectively, with an average transfusion of 2 units of blood (range 1-6 units). HHS improved by an average of 34 points, with excellent result in 64.3% of patients. Two implants failed, one due to traumatic ceramic head fracture 64 months after surgery, and one due to mobilization of the cup on the second post-operative day. CONCLUSION: THA surgery in Paget's patients is a safe procedure, and implant survival is only partly affected by bone remodelling and choice of fixation. The post-operative functional outcome is largely similar to that of other patients. Bleeding-related complications are the main complications; a careful pharmacological strategy should be recommended to decrease the risk of transfusions and of HO development. LEVEL OF EVIDENCE: Level III.

Fibrous Dysplasia, Paget's Disease of Bone, and Other Uncommon Sclerotic Bone Lesions of the Craniofacial Bones.

Imaging studies of the brain, head and neck, sinuses, and dental computed tomography are among the most frequently performed procedures in radiologic departments. Systematic evaluation in the bone window may reveal common and uncommon sclerotic osseous abnormalities of the craniofacial skeleton.Most of these findings are incidental and unrelated to the initial clinical indications. Sporadically symptoms may arise due to lesional mass effect with compression on adjacent structures and neuroforaminal encroachment, resulting in proptosis, vision, or hearing loss. Other symptoms include craniofacial deformity, mandibular occlusion deformity, and local pain.This article reviews the most common disorders characterized by an increased bone density involving the craniofacial bones including fibrous dysplasia, Paget's disease of bone, meningioma with associated hyperostosis, and osteoma. Finally, typical examples of rarer sclerosing bone dysplasias are discussed as well.Emphasis is placed on imaging features and the differential diagnosis.

Paget's Disease of Long Bones: Microstructural Analyses of Historical Bone Samples.

Although Paget's disease of bone (PDB) is the second most common metabolic bone disease, there is only limited information about the microarchitecture of affected bones. Therefore, the aim of this study was to determine cortical and trabecular bone properties in clinically relevant locations by microcomputed tomography (µCT). Ten femora and ten tibiae affected by Paget's disease taken from the Natural History Museum Vienna were compared to 13 femora and 10 tibiae of non-affected body donors. Digitization of the cortical and trabecular bone microarchitecture was performed with an X-ray-based µCT scanner. Additionally, semi-quantitative gradings of trabecular and cortical architectural parameters of the femora and the tibiae were generated. Microcomputed tomography images showed changes in the thickness of cortices, cortical porosity, and trabecularization of cortical structures. Moreover, severe disorganization of trabecular structures, trabecular defects, and thickening of (remaining) trabeculae were detected. Numerical cortical analyses showed lower total bone volume (BV) and lower BV in the outer region (66-100%) (- 36%, p = 0.004, and - 50%, p < 0.001, respectively), lower total volume (TV) in the outer region (66-100%) (- 42%, p < 0.001), lower total bone volume fraction (BV/TV) and BV/TV in the outer region (66-100%) (- 23%, and - 12%, p < 0.001, respectively), higher BV and TV in the middle region (33-66%) and higher BV/TV in the inner region (0-33%) (123%, p = 0.011, 147%, p = 0.010, and 33%, p = 0.025, respectively) in Pagetic compared to non-affected bones. Trabecular analyses showed higher BV/TV (96%, p = 0.008) and Tb.Th (43%, p = 0.004) in Pagetic compared to non-affected bones. There is a major and consistent structural alteration of PDB at cortical and trabecular sites in weight-bearing long bones. Our findings are relevant for the differential diagnosis of PDB and for the pathogenesis of associated complications, since the disorder produces abnormalities in the structure that might lead to bone fragility.

Hepatosplenomegaly, pneumopathy, bone changes and fronto-temporal dementia: Niemann-Pick type B and SQSTM1-associated Paget's disease in the same individual.

Data from exome sequencing show that a proportion of individuals in whom a genetic disorder is suspected turn out to have not one, but two to four distinct ones. This may require an evolution in our diagnostic attitude towards individuals with complex disorders. We report a patient with splenomegaly, pneumopathy, bone changes and fronto-temporal dementia (FTD). "Sea-blue histiocytes" in his bone marrow pointed to a lysosomal storage disease. Homozygosity for a pathogenic mutation in the SMPD1 gene confirmed Niemann-Pick disease type B (NPD-B). Mild cognitive impairment and abnormal brain FDG PET were consistent with FTD. We initially tried to fit the skeletal and neurologic phenotype into the NPD-B diagnosis. However, additional studies revealed a pathogenic mutation in the SQSTM1 gene. Thus, our patient had two distinct diseases; NPD-B, and Paget's disease of bone with FTD. The subsequent finding of a mutation in SQSTM1 gene ended our struggle to explain the combination of findings by a singular "unifying" diagnosis and allowed us to make specific therapeutic decisions. SQSTM1 mutations have been reported in association with FTD, possibly because of defective autophagy. Bisphosphonates may be beneficial for PDB, but since they are known to inhibit acid sphingomyelinase activity, we refrained from using them in this patient. While the principle of looking for unifying diagnosis remains valid, physicians should consider the possibility of co-existing multiple diagnoses when clinical features are difficult to explain by a single one. Accurate diagnostic work-up can guide genetic counseling but also lead to better medical management.

Acquired resistance to pamidronate treated effectively with zoledronate in juvenile Paget's disease.

Juvenile Paget's disease (JPD) is a rare autosomal recessive osteopathy. There is still a question about the most effective treatment modality in long-term prognosis. A 9-month-old boy who suffered from bone pain and deformities with a very high alkaline phosphatase level was diagnosed as JPD by radiographic findings. Genetic analysis showed a homozygous large deletion in TNFRSF11B gene encoding osteoprotegerin. Clinical improvement was observed with intravenous pamidronate therapy. However, the effect of drug reduced in time so the annual dose per kilogram body weight was increased after 2 years. Despite this increment, bone fractures developed and bone pain recurred with high-ALP levels, which suggested resistance to pamidronate. Switching to zoledronate resulted a significant improvement in bone findings radiographically and ALP level. Severe hypocalcemia requiring intravenous calcium treatment complicated the first dose of zoledronate, but not recurred thereafter. Intravenous pamidronate therapy is effective in reducing bone pain, improving bone deformities and motor development in infantile onset JPD. However, this effect can be transient. Switching to another bisphosphonate like zoledronate may provide long-term clinical and biochemical improvement as an alternative treatment in case of resistance to pamidronate therapy.

Paget's disease of the lumbar spine: decompressive surgery following 17 years of bisphosphonate treatment.

BACKGROUND: We present a rare case of Paget's disease (PD) with involvement of the lumbar spine over a period of 19 years. We discuss the diagnostic process to rule out alternative diagnoses and medical and surgical treatment strategies. CASE DESCRIPTION: A 58-year-old man first diagnosed with PD in 1998 with solid involvement of the 4th lumbar vertebra has been undergoing periodic examinations over a period of 18 years. Since then, the patient has been treated conservatively with bisphosphonates. When conservative treatment options have been exhausted, surgery was indicated due to a progressively reduced ability to walk. Surgery with undercutting decompression via laminotomy was performed. PD was confirmed by biopsy. Bisphosphonate treatment was continued pre- and postoperatively. Follow-up examinations showed an improvement in clinical outcome measures. CONCLUSIONS: Conservative treatment remains the gold standard for PD with spinal involvement. This patient had been asymptomatic on bisphosphonate therapy for almost 17 years, but presented with new onset back pain. In such cases, fracture and rare conversion into sarcoma must be ruled out, and biopsy should be performed even in the absence of signs of malignancy. Currently, there are no clear treatment recommendations available in the literature regarding cases of PD with expansive growth and involvement of the spinal canal causing neurologic deficits. Furthermore, laminectomy has been shown to cause complications in up to 27% of cases with the risk of early postoperative death. In contrast, extended laminotomy and undercutting decompression should be considered.

Clinical and Microstructural Findings in Paget Disease of the Entire Mandible.

Paget disease of bone (PDB) is a chronic progressive bone disorder characterized by localized increased bone turnover and focal areas of woven bone formation. Although skull involvement is common, PDB very rarely affects the mandible. This report describes the clinical and histologic findings in a 75-year-old patient with PDB involving the mandible. Microstructural analyses showed an altered quality of the bone microstructure and calcium depletion of the affected bone. Differential diagnosis of PDB affecting the mandible is discussed.

The lucent (CT) and enhancing (MR) rim, a sign of Paget's disease of the skull: case report.

Osteoporosis circumscripta is sometimes observed at the skull vault and corresponds to the initial stage of Paget's disease of the bone. Differentiating osteoporosis circumscripta from other reasons for osteolytic images of the vault may be difficult. We report a case of osteoporosis circumscripta of the frontal bone. A lucent rim seen on CT scan, which was enhanced on gadolinium-enhanced MRI, delineated the abnormal bone. The patient was a 50-year-old woman who had CT scans of the skull for chronic sinusitis. Pathology examination showed typical bone changes of Paget's disease. The lucent and enhancing rim sign may help in differentiating Paget's disease from other conditions.

Paget's disease of jaw bones as primary manifestation: A case report of a proper diagnosis made by general dentist.

OBJECTIVE: To present a case of early diagnosis mandibular Paget's disease of bone (PDB), recognised by a general dentist. BACKGROUND: PDB is responsible of rapid bone resorption and disorganised bone formation. MATERIALS AND METHODS: The patient was a 72-year-old female patient complaining of dental malposition and blatant prognathism. CONCLUSION: Clinicians should consider PDB in differential diagnosis for an elderly patient undergoing unexplained alteration in face profile and occlusion.

[Inclusion Body Myopathy, Paget's Disease, and Fronto-temporal Dementia: a VCP-related Multi-systemic Proteinopathy]. / Einschlusskörpermyopathie, Paget-Krankheit und frontotemporale Demenz: eine VCP-bedingte, multisystemische Proteinopathie.

Mutations of the human VCP gene, which encodes the V: alosin C: ontaining P: rotein (synonyms: p97, TER ATPase), are associated with various multi-systemic protein aggregation diseases. We report on a patient with progressive myopathy and incipient cognitive deficits. A diagnostic muscle biopsy revealed an inclusion body myopathy with protein aggregates. Magnetic resonance imaging and F18-positron-emission-tomography disclosed a fronto-temporal atrophy and glucose hypometabolism of the frontal and temporal lobes, respectively. Based on the clinical findings, a genetic analysis was performed which revealed a heterozygous c.277C>T (p.Arg93Cys) mutation of the VCP gene, thus confirming the diagnosis of IBMPFD (I: nclusion B: ody M: yopathie with P: aget Disease of the Bones and F: ronto-temporal D: ementia).

Long-Term Bone Scintigraphy Results After Intravenous Zoledronate in Paget's Disease of Bone.

Zoledronate produces long-term normalization of biochemical markers in Paget's disease but whether this implies the absence of active disease is unknown. We have determined whether bone scintigraphy, a more sensitive index of disease activity, is also normalized ≥5 years after treatment with zoledronate. A consecutive case series of 11 individuals with Paget's disease treated with zoledronate 5 mg ≥5 years previously is reported. Eight patients received a single zoledronate infusion and were assessed 55-120 months later. Bone scintigraphy showed no evidence of active disease in four of these patients, and there was minimal residual disease activity in the other four. Three other patients required second infusions because of evidence of ongoing disease activity. In two of these, scintigraphy was normal ~90 months after their second infusions. In the third, further follow-up is not available. Procollagen-I N-terminal propeptide and total alkaline phosphatase were normal in all subjects at the time of bone scintigraphy. This case series confirms the high rate of response of Paget's disease to zoledronate, demonstrates the much greater sensitivity of scintigraphy compared with biochemical markers in detecting ongoing disease activity, and indicates that about one-third may be scintigraphically "cured" after one infusion; one-third have scintigraphically trivial disease activity subsequently, and the balance may require a second infusion. Scintigraphic "cure" is achievable after second infusions. Scintigraphy has an important place in the long-term management of Paget's patients following zoledronate, and should guide follow-up decisions in those with normal biochemical markers.

Management of Paget's Disease of the Calcaneum.

The calcaneum is not the most common site for Paget's disease of bone, with only a few reports of monostotic involvement. We present 2 cases of Paget's disease of bone affecting the calcaneus, present an overview of the published data, and describe our management of these interesting cases.