Hepatitis C-associated Osteosclerosis (HCAO): Long-Term Follow-Up of a New Case Recovered After Antiviral Treatment.

Hepatitis C-associated osteosclerosis (HCAO) is a very rare condition that can be observed in a small number of patients with Hepatitis C Virus (HCV) infection. HCAO is usually characterized by widespread bone sclerosis, associated with severe bone pain, and increased levels of bone turnover markers, especially alkaline phosphatase (ALP). In this report, we present the case of a 55-year-old woman who was affected by HCV and came to our attention for severe and diffuse bone pain. Radiological studies showed bone sclerosis, and bone mineral density (BMD) was markedly increased, as well as serum ALP levels. The patient was initially treated with intravenous pamidronate, which provided only a transient benefit on clinical symptoms. Then antiviral therapy for HCV (interferon-alfa and ribavirin) was started and it was effective in making the viral load undetectable. After a long follow-up period, we observed a persistent remission of bone pain, a reduction in BMD together with a progressive trend toward the normalization of bone turnover markers. In conclusion, HCAO, although rare, should be considered among the potential causes of increased bone mass in patients with HCV infection, and treatment for the underlying infection may be effective in controlling the manifestations of this disease.

Bi-allelic CSF1R Mutations Cause Skeletal Dysplasia of Dysosteosclerosis-Pyle Disease Spectrum and Degenerative Encephalopathy with Brain Malformation.

Colony stimulating factor 1 receptor (CSF1R) plays key roles in regulating development and function of the monocyte/macrophage lineage, including microglia and osteoclasts. Mono-allelic mutations of CSF1R are known to cause hereditary diffuse leukoencephalopathy with spheroids (HDLS), an adult-onset progressive neurodegenerative disorder. Here, we report seven affected individuals from three unrelated families who had bi-allelic CSF1R mutations. In addition to early-onset HDLS-like neurological disorders, they had brain malformations and skeletal dysplasia compatible to dysosteosclerosis (DOS) or Pyle disease. We identified five CSF1R mutations that were homozygous or compound heterozygous in these affected individuals. Two of them were deep intronic mutations resulting in abnormal inclusion of intron sequences in the mRNA. Compared with Csf1r-null mice, the skeletal and neural phenotypes of the affected individuals appeared milder and variable, suggesting that at least one of the mutations in each affected individual is hypomorphic. Our results characterized a unique human skeletal phenotype caused by CSF1R deficiency and implied that bi-allelic CSF1R mutations cause a spectrum of neurological and skeletal disorders, probably depending on the residual CSF1R function.

Congenital lipodystrophy induces severe osteosclerosis.

Berardinelli-Seip congenital generalized lipodystrophy is associated with increased bone mass suggesting that fat tissue regulates the skeleton. Because there is little mechanistic information regarding this issue, we generated "fat-free" (FF) mice completely lacking visible visceral, subcutaneous and brown fat. Due to robust osteoblastic activity, trabecular and cortical bone volume is markedly enhanced in these animals. FF mice, like Berardinelli-Seip patients, are diabetic but normalization of glucose tolerance and significant reduction in circulating insulin fails to alter their skeletal phenotype. Importantly, the skeletal phenotype of FF mice is completely rescued by transplantation of adipocyte precursors or white or brown fat depots, indicating that adipocyte derived products regulate bone mass. Confirming such is the case, transplantation of fat derived from adiponectin and leptin double knockout mice, unlike that obtained from their WT counterparts, fails to normalize FF bone. These observations suggest a paucity of leptin and adiponectin may contribute to the increased bone mass of Berardinelli-Seip patients.

Vitamin D receptor-mediated skewed differentiation of macrophages initiates myelofibrosis and subsequent osteosclerosis.

Myelofibrosis in myeloproliferative neoplasms (MPNs) with mutations such as JAK2V617F is an unfavorable sign for uncontrollable disease progression in the clinic and is complicated with osteosclerosis whose pathogenesis is largely unknown. Because several studies have revealed that macrophages are an indispensable supporter for bone-forming osteoblasts, we speculated that macrophages might play a significant role in the proliferation of collagen-producing myofibroblasts in marrow fibrotic tissues. Here, we show that myelofibrosis critically depends on macrophages whose differentiation is skewed by vitamin D receptor (VDR) signaling. In our novel myelofibrosis model established by transplantation of VDR+/+ hematopoietic stem/progenitor cells into VDR-/- mice, donor-derived F4/80+ macrophages proliferated together with recipient-derived α-smooth muscle actin-positive myofibroblasts, both of which comprised fibrotic tissues with an indistinguishable spindle-shaped morphology. Interfering VDR signals, such as low vitamin D diet and VDR deficiency in donor cells as well as macrophage depletion prevented myelofibrosis in this model. These interventions also ameliorated myelofibrosis in JAK2V617F-driven murine MPNs likely in a transforming growth factor-ß1- or megakaryocyte-independent manner. These results suggest that VDR and macrophages may be novel therapeutic targets for MPNs with myelofibrosis.

Diffuse osteosclerosis as a presentation of recurrent breast cancer: role of endothelin 1.

We report a 46-yr-old woman with a history of breast cancer who presented with diffuse myalgias, bone pain, and osteosclerosis. She was found to have recurrent breast cancer producing endothelin-1. INTRODUCTION: Acquired osteosclerosis can be caused by various disorders. Endothelin -1 is believed to contribute to osteosclerosis caused by breast cancer. METHODS: Although the bone marrow biopsy did not reveal breast cancer, she developed skin lesions consistent with metastatic breast cancer. She ultimately died from progressive disease. At autopsy immunohistochemistry for endothelin-1 was performed on a section from the L5 vertebral body. RESULTS: The section from the L5 vertebral body showed small foci of cells consistent with metastatic carcinoma and a prominent sclerotic response. Immunohistochemistry for endothelin-1 was strongly positive. CONCLUSIONS: Recurrent breast cancer may present with diffuse osteosclerosis. Endothelin-1 may be a paracrine factor responsible for increased bone formation and osteosclerosis.

Finite-element analysis of the proximal tibial sclerotic bone and different alignment in total knee arthroplasty.

BACKGROUND: Despite potential for improving patient outcomes, studies using three-dimensional measurements to quantify proximal tibial sclerotic bone and its effects on prosthesis stability after total knee arthroplasty (TKA) are lacking. Therefore, this study aimed to determine: (1) the distribution range of tibial sclerotic bone in patients with severe genu varum using three-dimensional measurements, (2) the effect of the proximal tibial sclerotic bone thickness on prosthesis stability according to finite-element modelling of TKA with kinematic alignment (KA), mechanical alignment (MA), and 3° valgus alignment, and (3) the effect of short extension stem augment utilization on prosthesis stability. METHODS: The sclerotic bone in the medial tibial plateau of 116 patients with severe genu varum was measured and classified according to its position and thickness. Based on these cases, finite-element models were established to simulate 3 different tibial cut alignments with 4 different thicknesses of the sclerotic bone to measure the stress distribution of the tibia and tibial prosthesis, the relative micromotion beneath the stem, and the influence of the short extension stem on stability. RESULTS: The distribution range of proximal tibial sclerotic bone was at the anteromedial tibial plateau. The models were divided into four types according to the thickness of the sclerotic bone: 15 mm, 10 mm, 5 mm, and 0 mm. The relative micromotion under maximum stress was smallest after MA with no sclerotic bone (3241 µm) and largest after KA with 15 mm sclerotic bone (4467 µm). Relative micromotion was largest with KA and smallest with MA in sclerotic models with the same thickness. Relative micromotion increased as thickness of the sclerotic bone increased with KA and MA (R = 0.937, P = 0.03 and R = 0.756, P = 0.07, respectively). Relative micromotion decreased with short extension stem augment in the KA model when there was proximal tibial sclerotic bone. CONCLUSIONS: The influence of proximal tibial sclerotic bone on prosthesis's stability is significant, especially with KA tibial cut. Tibial component's short extension stem augment can improve stability.

Systemic Changes Affecting the Morphology of Calvarial Bone.

Plastic surgeons are frequently consulted to evaluate concerns about a patient's skull. Imaging studies often reveal abnormalities in bone morphology, from increased porosity to sclerotic changes. While focal findings imply a benign or malignant neoplasm, the etiology of more diffuse findings can be more varied, making the correct diagnosis challenging. The present review summarizes the differential diagnosis of osseous lesions of the calvarium that affect the bone and contribute to changes seen on imaging studies.

Osteosclerosis associated with hepatitis C.

We describe the first Finnish case of hepatitis C associated osteosclerosis. In which the patient's bone symptoms and bone density were resolved with hepatitis C treatment. Suspecting the possibility of osteosclerosis underlying bone pains in a hepatitis C patient is well-founded, although osteoporotic fractures are a more common problem.

[Evaluation of five years of treatment of Erdheim-Chester disease with anakinra: case report and overview of literature]. / Hodnocení petileté lécby Erdheimovy-Chesterovy nemoci anakinrou - kazuistika a prehled literatury.

Erdheim-Chester disease is a histiocytic neoplasm of diseases from the group of non-Langerhans-cell histiocytoses, formed by infiltrates of foamy histiocytes. These pathological histiocytes produce pro-inflammatory cytokines. Therefore Erdheim-Chester disease is called inflammatory histiocytary neoplasm. The disease is accompanied by clinical symptoms of systemic inflammatory response, i.e. B symptoms. Imaging examinations detect typical osteosclerotic changes affecting diaphyses and metaphyses of the lower long bones and fibrotic changes which affect the aorta wall and the vessels leading from it. Also characteristic are perirenal fibrotic changes spreading in the retroperitoneum. They can cause serious complications - hydronephrosis with all its consequences. The therapy for this disease was not satisfactory in the previous years. Conventional chemotherapy or glucocorticoids do not bring any substantial and long-term improvement. Considering cytostatic drugs, only 2-chlorodeoxyadenosine (cladribine) is effective, though not in all patients. We have only reached complete remission through 2-chlorodeoxyadenosine in one of our two patients, which now lasts more than 5 years, while cladribine in the same patient did effect the reduction of infiltrates into the CNS, but it did not achieve abatement of the disease activity in other locations as shown by PET/CT with the application of the radio-pharmaceutical fluorodeoxyglucose (FDG). Another effective medicine for patients with Erdheim-Chester disease is interferon α. However its long-term administration is associated with multiple adverse effects and so we did not test it in the described patient. The introduction of anakinra, the interleukin-1 receptor blocker, to therapy brought a new hope for these patients. We are describing the patient who has been treated with anakinra for more than 5 years. The patient applies 1 ampoule of 100 mg subcutaneously per day. This treatment completely removed systemic B symptoms, relieved bone pains and attained normalization of all findings that signalled systemic inflammatory response. The treatment effect is regularly checked by CT imaging of the abdomen and by FDG-PET/CT examinations. The retroperitoneal fibrotic changes gradually regressed during the 5 years of anakinra treatment, as documented by the pictures in the text. Low-dose CT imaging which was part of the PET/CT examination, identified many osteosclerotic lesions in the skeleton, mainly in the legs, with an increased accumulation of 18F-fluorodeoxyglucose (FDG). Osteosclerotic lesions remain well visible at repeated examinations. Still during the course of the 5-year period the FDG accumulation in them decreased, as shown by the pictures in the text. Anakinra treatment has a character of maintenance therapy. The BRAFV600E mutation was not proven in the described patient, therefore we did not test vemurafenib treatment. CONCLUSION: anakinra effected regression of fibrotic changes in the retroperitoneum and disappearance of B symptoms as well as decrease in FDG accumulation at FDG-PET/CT examination.Key words: anakinra - Erdheim-Chester disease - cladribine - retroperitoneal fibrosis - vemurafenib.

Mid-term clinical results of primary total knee arthroplasty using metal block augmentation and stem extension in patients with rheumatoid arthritis.

BACKGROUND: Despite recent advancements in rheumatoid arthritis (RA) pharmacotherapy, surgeons still encounter severely damaged knees. The purpose of the present study was to analyze the mid-term clinical results of total knee arthroplasty (TKA) with metal block augmentation and stem extension. METHODS: A total of 26 knees in 21 patients who underwent primary TKA with metal block augmentation and stem extension were retrospectively reviewed. All patients with a mean age of 63 years had RA for a mean duration of 15 years. Functional and radiographic results as well as complications were evaluated at the mean follow-up period of 6 years after TKA. Eight knees were lost follow-up after the two-year evaluation. RESULTS: Tibial bone defects with average depth of 19 mm were preoperatively recognized in all 26 knees. The postoperative joint line was reconstructed on average 11 mm above the fibular head using average thickness of 11 mm tibial inserts and 9 mm metal blocks with stem extension. Significant improvements (p < 0.05 for all comparisons) were observed postoperatively in maximum extension angle from -10° to -1°, range of motion from 101 ° to 115 °, and Knee Society Score (knee score/function score) from 35/18 to 90/64. Non-progressive radiolucent lines beneath the metal block and osteosclerotic changes around the medullary stem were found in 16 knees (62%) and 14 knees (54%), respectively. There was two failures (8%): fragile supracondylar femur fractures and knee instability. No knees showed any radiographic implant loosening, dislocation, polyethylene insert breakage, peroneal palsy, or infection. CONCLUSIONS: Primary TKA with metal block augmentation and stem extension could effectively restore function in RA patients with advanced forms of knee joint destruction, and be reliable and durable for a mean postoperative period of 6 years. Further study is needed to determine the long-term results of TKA using metal block augmentation and stem extension.

POEMS Syndrome: A Rare Disease With A Challenging Diagnosis.

A complex conglomerate of symptoms, signs, and abnormalities are present with POEMS syndrome, making the diagnosis, management and follow-up a challenge. Recognizing the disease early on may be difficult. Many patients are initially misdiagnosed as having others disorders, for example: multiple myeloma. There is no standard treatment for patients diagnosed with POEMS syndrome.

Diffuse osteosclerosis in a patient with prostate cancer.

A 61-year-old man was referred to our outpatient clinic because of severe bilateral upper leg pain for 1 year. On admission, the patient had anemia and a high serum alkaline phosphatase level. Lumbar and femoral neck T-scores were +10.5 and +9.6, respectively. His radius 33 % T-score was -2.8. Plain radiographs of the patient's pelvis, spine, and long bones revealed osteosclerosis. The patient had previously undergone a prostate biopsy, which showed prostate adenocarcinoma (Gleason score 3 + 4). The patient's total and free prostate-specific antigen were very high. According to previous records, the patient did not have anemia, and his serum alkaline phosphatase (ALP) level was normal. An abdominal radiograph taken 2 years earlier revealed a normal spine and pelvic bone. Bone scintigraphy yielded nontypical findings for prostate cancer metastasis. Computed tomography of the patient's thorax and abdomen showed heterogeneous sclerotic areas in all bones consistent with prostate cancer metastasis. A bone marrow biopsy disclosed disseminated carcinomatosis of bone marrow in association with prostate cancer. Clinicians should be aware of the possibility of prostate malignancy as a cause of high bone mineral density (BMD), even in the absence of typical localized findings on plain radiographs.

An uncommon cause of acquired osteosclerosis in adults: hepatitis C-associated osteosclerosis.

Hepatitis C-associated osteosclerosis (HCAO) is a rare sclerosing bone condition characterized by debilitating, predominantly lower extremity bone pain, accelerated bone turnover, and a generalized increase in histologically normal trabecular and cortical bone tissue. Herein we report the clinical presentation and imaging results of the 19th case of HCAO. Clinicians, particularly those caring for a population at risk for HCV infection, should be aware of this uncommon condition. The etio-pathogenesis of HCAO remains obscure but may bear important lessons in bone biology that could lead to new treatment options for osteoporosis.

[Diagnosis of Erdheim-Chester disease following a traumatic fracture]. / Diagnostic de maladie d'Erdheim-Chester à la suite d'une fracture traumatique.

We describe the case of a woman with the diagnosis of Erdheim-Chester disease following an upper limb traumatic fracture. A 65-year-old woman presents to the emergency department for left shoulder and right ankle pain, she admits recent multiple falls. Imaging shows a left trochiter fracture and osteosclerotic lesions in the upper and lower limbs. Bone biopsy confirms the suspicion of Erdheim-Chester disease. Erdheim-Chester disease is a rare systemic non- Langerhans cell histiocytosis of the middle-aged adult. The most common characteristic is bilateral and symmetric osteosclerotic lesions in long bones. Pathological examination provides the definitive diagnosis. Imaging and clinical biology assess the extent of the disease. Treatment must be decided on a case-to-case basis taking into account patient's symptoms.

Monoclonal gammopathy of clinical signifi cance with osteosclerotic lesions - a case report and a literature review.

INTRODUCTION: Multiple myeloma is a common plasma cell neoplasia usually accompanied by the formation of osteolytic foci, whereas osteosclerotic myeloma is a very rare form of plasma cell dyscrasia. When osteosclerotic myeloma is detected, osteosclerotic foci are usually part of the POEMS syndrome. Osteosclerotic myeloma without other manifestations of the POEMS syndrome is an unusual finding. CASE DESCRIPTION: In a 46-year-old woman, osteosclerotic changes of the temporoparietal region caused soft tissue induration over this lesion, which initiated further investigation. Imaging studies subsequently showed multiple osteosclerotic foci in the skull. Examination of blood proteins revealed 8 g/L of IgG-lambda monoclonal immunoglobulin, subclass IgG1. In search of the cause of the osteosclerotic changes, FDG-PET/CT was performed, which revealed no FDG accumulation, i.e., no other tumor (breast or stomach cancer). Low-dose CT showed irregular bone structure, but not significant osteolytic or osteosclerotic foci. To map the extent of osteosclerotic changes, NaF-PET/CT imagination followed, which revealed multiple spots with high fluoride accumulation. A parietal bone biopsy showed osteosclerosis with minor clonal plasma cell infiltration. Trepanobioptic bone marrow sampling revealed an infiltration of bone marrow with atypical plasma cells in 8%. Flow-cytometric examination of bone marrow showed 0,37% of plasma cells, however predominantly (91%) clonal with lambda expression. MRI of the brain identified asymptomatic meningeal thickening. There was no evidence of POEMS syndrome in the patient; thus, we concluded the diagnosis as monoclonal gammopathy of clinical significance with osteosclerosis which was previously termed osteosclerotic multiple myeloma. CONCLUSION: Monoclonal gammopathy of clinical significance (MGCS) with osteosclerotic skeletal changes, documented on CT and multiple foci with intensive osteoneogenesis, documented on NaF-PET/CT without evidence of POEMS syndrome, is an extremely rare form of plasma cell dyscrasia. This publication documents the unique clinical manifestations of IgG-lambda type plasma cell proliferation without signs of POEMS syndrome and the role of NaF-PET/CT imaging. Classification of this disease as MGSC with osteosclerotic manifestations is more consistent with the indolent nature of the disease with a significantly better prognosis, compared with multiple myeloma.

New advances in the diagnosis and treatment of POEMS syndrome.

POEMS syndrome is a clonal plasma cell disease characterized by polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes. Significant advances have been made in the diagnosis and treatment of POEMS syndrome over the last decade. Herein, the diagnostic criteria and characteristic features are reviewed, focusing the role of characteristic features in early diagnoses. Autologous peripheral blood stem cell transplantation has become the first-line treatment for younger patients with normal organ function. Autologous transplantation has resulted in a high response rate and durable remission. Moreover, transplantation-related morbidity and mortality has been significantly reduced over the past 5 years. Induction therapy before transplantation may improve the harvest of stem cells and decrease transplantation-related morbidity. Melphalan and dexamethasone is an effective and well-tolerated treatment for older patients or those with organ dysfunction. Novel agents may also offer benefits to patients with a poor performance status or renal dysfunction, and transform transplantation eligibility.

Hereditary deletion of the entire FAM20C gene in a patient with Raine syndrome.

Raine syndrome is an autosomal recessive disorder caused by mutations in the FAM20C gene that is characterized by generalized osteosclerosis with periosteal new bone formation and distinctive craniofacial dysmorphism. We report on a child who is homozygous for a 487-kb deletion in 7p22.3 that contains FAM20C. Both parents were heterozygous for the deletion. Our patient had the common craniofacial features as well as, uncommon features such as protruding tongue, short stature, and hypoplastic distal phalanges. In addition, he had wormian bones and pyriform aperture stenosis, features that are usually under diagnosed. It is clear that Raine syndrome has a wide range of expression and may not be lethal in the neonatal period. Furthermore, Raine cases due to whole gene deletion do not seem to have a major difference in the phenotype over those caused by various mutations.