Sebastian Butscheidt

Denosumab is effective in the treatment of bone marrow oedema syndrome.

Bone marrow oedema (BMO) syndrome describes a painful condition with increase of interstitial fluid within bone and is often lately diagnosed due to unspecific symptoms. The underlying causes are diverse while it is widely assumed that in cases of BMO local bone resorption is increased. Denosumab, a human monoclonal antibody that binds to the receptor activator of nuclear factor kappa-B ligand (RANKL) inhibits osteoclastic bone resorption and is commonly administered in the treatment of osteoporosis. Besides one previous case report, its clinical effectiveness in the treatment of bone marrow oedema has not been elucidated. We treated 14 patients with primary (idiopathic) bone marrow oedema of the lower extremity with single dose denosumab application. Mean time between onset of pain and therapy was 155days. MRI scans were performed for initial diagnosis, and 6-12 weeks after denosumab injection. Vitamin D and calcium homeostasis were strived to be balanced before initiation of therapy. Furthermore bone status was analysed using Dual-energy X-ray absorptiometry (DXA) and extended bone turnover serum markers. After 6-12 weeks, BMO dissolved partly or completely in 93%, while a complete recovery was observed in 50% of the individuals. Visual analogue scale (VAS) evaluation revealed a significant decrease in pain level. Furthermore, bone turnover decreased significantly after treatment. No adverse reactions were reported. In conclusion, our retrospective analysis shows that denosumab is highly effective in the treatment of bone marrow oedema and therefore represents an alternative treatment option.

CT Pulmonary Angiography at Reduced Radiation Exposure and Contrast Material Volume Using Iterative Model Reconstruction and iDose4 Technique in Comparison to FBP

Purpose To assess image quality of CT pulmonary angiography (CTPA) at reduced radiation exposure (RD-CTPA) and contrast medium (CM) volume using two different iterative reconstruction (IR) algorithms (iDose4 and iterative model reconstruction (IMR)) in comparison to filtered back projection (FBP). Materials and Methods 52 patients (body weight < 100 kg, mean BMI: 23.9) with suspected pulmonary embolism (PE) underwent RD-CTPA (tube voltage: 80 kV; mean CTDIvol: 1.9 mGy) using 40 ml CM. Data were reconstructed using FBP and two different IR algorithms (iDose4 and IMR). Subjective and objective image quality and conspicuity of PE were assessed in central, segmental, and subsegmental arteries. Results Noise reduction of 55% was achieved with iDose4 and of 85% with IMR compared to FBP. Contrast-to-noise ratio significantly increased with iDose4 and IMR compared to FBP (p<0.05). Subjective image quality was rated significantly higher at IMR reconstructions in comparison to iDose4 and FBP. Conspicuity of central and segmental PE significantly improved with the use of IMR. In subsegmental arteries, iDose4 was superior to IMR. Conclusions CTPA at reduced radiation exposure and contrast medium volume is feasible with the use of IMR, which provides improved image quality and conspicuity of pulmonary embolism in central and segmental arteries.

Comparison of image quality and visibility of normal and abnormal findings at submillisievert chest CT using filtered back projection, iterative model reconstruction (IMR) and iDose(4)™.

OBJECTIVE To compare both image quality and visibility of normal and abnormal findings at submillisievert chest CT (smSv-CT) using filtered back projection (FBP) and the two different iterative reconstruction (IR) techniques iterative model reconstruction (IMR) and iDose4™. MATERIALS AND METHODS This institutional review board approved study was based on retrospective interpretation of clinically indicated acquired data. The requirement to obtain informed consent was waived. 81 patients with suspected pneumonia underwent smSv-CT (Brilliance iCT, Philips Healthcare; mean effective dose: 0.86±0.2mSv). Data were reconstructed using FBP and two different IR techniques iDose4™ and IMR (Philips Healthcare) at various iteration levels. Objective image noise (OIN) was measured. Two experienced readers independently assessed all images for image noise, image appearance and visibility of normal anatomic and abnormal findings. A random intercept model was used for statistical analysis. RESULTS Compared to FBP and iDose4™, IMR reduced OIN up to 88% and 72%, respectively (p<0.001). A mild blotchy image appearance was seen in IMR images, affecting diagnostic confidence. iDose4™ images provided satisfactory to good image quality for visibility of normal and abnormal findings and were superior to FBP (p<0.001). IMR images were significantly inferior for visibility of normal structures compared to iDose4™, while being superior for visibility of abnormal findings except for reticular pattern (p<0.001). CONCLUSION IMR results for visibility of normal and abnormal lung findings are heterogeneous, indicating that IMR may not represent a priority technique for clinical routine. iDose4™ represents a suitable method for evaluation of lung tissue at submillisievert chest CT.

Disease Duration and Stage Influence Bone Microstructure in Patients With Primary Biliary Cholangitis: BONE MICROSTRUCTURE IN PBC PATIENTS

Primary biliary cholangitis (PBC) is known to be a major risk factor for osteoporosis reflected by a reduction of bone mineral density (BMD). However, both the extent of the macro‐ and microstructural alterations of bone as well as the causative factors are unknown. We have retrospectively analyzed a total of 96 patients with PBC and 53 healthy controls matched for age, sex, and body mass index. In addition to dual‐energy X‐ray absorptiometry (DXA) measurements at the lumbar spine and hip, high‐resolution peripheral quantitative computed tomography (HR‐pQCT) was used to assess the geometric, volumetric, and microstructural changes of bone at the distal radius and tibia. Furthermore, serum analyses and measures of disease duration and stage including transient elastography were performed. Total, cortical, and trabecular volumetric BMD as well as geometric parameters were significantly reduced in PBC patients. Microstructural analysis revealed a significantly lower cortical thickness (p < 0.001) and bone volume per tissue volume (p < 0.001) in the radius and tibia but unchanged trabecular number in patients with PBC (radius: p = 0.42; tibia: p = 0.12). Multivariate regression models pointed out that disease duration and stage are the primary factors that are independently associated with bone loss in PBC. A subgroup analysis of patients with additional autoimmune hepatitis (AIH) revealed no significant changes in bone structure compared with PBC only. Taken together, PBC patients demonstrate severe alterations in bone microstructure that are positively associated with disease duration and stage. By applying HR‐pQCT in the distal radius and tibia, a combined bone loss syndrome expressed by a predominant decrease in BMD and cortical thickness could be detected.

Severe bone loss and multiple fractures in SCN8A-related epileptic encephalopathy

Mutations in the SCN8A gene encoding the neuronal voltage-gated sodium channel Nav1.6 are known to be associated with epileptic encephalopathy type 13. We identified a novel de novo SCN8A mutation (p.Phe360Ala, c.1078_1079delTTinsGC, Exon 9) in a 6-year-old girl with epileptic encephalopathy accompanied by severe juvenile osteoporosis and multiple skeletal fractures, similar to three previous case reports. Skeletal assessment using dual energy X-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HR-pQCT) and serum analyses revealed a combined trabecular and cortical bone loss syndrome with elevated bone resorption. Likewise, when we analyzed the skeletal phenotype of 2week-old Scn8a-deficient mice we observed reduced trabecular and cortical bone mass, as well as increased osteoclast indices by histomorphometric quantification. Based on this cumulative evidence the patient was treated with neridronate (2mg/kg body weight administered every 3months), which fully prevented additional skeletal fractures for the next 25months. Taken together, our data provide evidence for a negative impact of SCN8A mutations on bone mass, which can be positively influenced by anti-resorptive treatment.

Mutational analysis uncovers monogenic bone disorders in women with pregnancy-associated osteoporosis: three novel mutations in LRP5, COL1A1, and COL1A2

SummaryPregnancy was found to be a skeletal risk factor promoting the initial onset of previously unrecognized monogenic bone disorders, thus explaining a proportion of cases with pregnancy-associated osteoporosis. Therapeutic measures should focus in particular on the normalization of the disturbed calcium homeostasis in order to enable the partial skeletal recovery.IntroductionPregnancy-associated osteoporosis (PAO) is a rare skeletal condition, which is characterized by a reduction in bone mineral density (BMD) in the course of pregnancy and lactation. Typical symptoms include vertebral compression fractures and transient osteoporosis of the hip. Since the etiology is not well understood, this prospective study was conducted in order to elucidate the relevance of pathogenic gene variants for the development of PAO.MethodsSeven consecutive cases with the diagnosis of PAO underwent a skeletal assessment (blood tests, DXA, HR-pQCT) and a comprehensive genetic analysis using a custom-designed gene panel.ResultsAll cases showed a reduced BMD (DXA T-score, lumbar spine − 3.2 ± 1.0; left femur − 2.2 ± 0.5; right femur − 1.9 ± 0.5), while the spine was affected more severely (p < 0.05). The trabecular and cortical thickness was overall reduced in HR-pQCT, while the trabecular number showed no alterations in most cases. The genetic analysis revealed three novel mutations in LRP5, COL1A1, and COL1A2.ConclusionOur data show that previously unrecognized monogenic bone disorders play an important role in PAO. Pregnancy should be considered a skeletal risk factor, which can promote the initial clinical onset of such skeletal disorders. The underlying increased calcium demand is essential in terms of prophylactic and therapeutic measures, which are especially required in individuals with a genetically determined low bone mass. The implementation of this knowledge in clinical practice can enable the partial recovery of the skeleton. Consistent genetic studies are needed to analyze the frequency of pathogenic variants in women with PAO.

Skeletal dissemination in Paget’s disease of the spine

PurposePaget’s disease of bone (PDB) is a common skeletal disorder that is associated with locally increased bone turnover, skeletal deformity and pain. We report a case of skeletal dissemination in PDB of the spine.MethodsCase report.ResultsA 46-year-old former professional athlete suffered from disseminated PDB throughout the spine and hips after various surgical interventions including spondylodesis, bone grafting and bone morphogenetic protein (rhBMP-2) administration. Only intravenous zoledronic acid prevented the further progression of skeletal dissemination, which was expressed by a normalization of (bone-specific) alkaline phosphatase levels. The biopsy obtained from the lumbar spine confirmed the diagnosis of PDB in the absence of malignant transformation.ConclusionsWe outline skeletal dissemination as a possibly surgery-related complication in a patient with PDB in the lumbar spine. Bisphosphonates remain the treatment of first choice in PDB and surgical interventions should be considered very carefully.

Pulmonary cement embolism is not associated with the cause of death in a post-mortem cohort of cement-augmented interventions in the spine

AbstractPurposeComplications of cement-augmented interventions (e.g., kyphoplasty) in the spine include local cement leakage and pulmonary cement embolisms (PCE). This study was conducted to determine their extent in a unique post-mortem cohort.MethodsRetrospective analysis of post-mortem whole-body CT scans and review of autopsy results in 29 consecutive cases with cement-augmented interventions in the spine. PCE findings were graded based on cement deposits: grade 0 (no PCE), grade 1 (1-3 PCE), grade 2 (4-6 PCE), and grade 3 (> 6 or branch-shaped PCE). Bone and lung tissue specimens were obtained in representative cases to confirm the findings histologically.ResultsLocal cement leakage was detected in 69%: intravenous (34%), intervertebral (31%), intraspinal (14%), and retrograde (17%). Lung sections showed PCE in 52%: grade 0 (48%), grade 1 (31%), grade 2 (10%), and grade 3 (10%). Matching with autopsy findings revealed that none of the cases died due to the impact of PCE.ConclusionsThe presented data reveal a high frequency of PCE making it a notable finding—especially since not only single but also branch-like embolisms were detected. Thus, it is of great importance that none of the causes of death were related to the impact of PCE. Nevertheless, it is crucial to consider the underlying diseases for increased PCE risk and to apply latest surgical techniques and preventive measures.Graphical abstract These slides can be retrieved under Electronic Supplementary material.

Comparison of Bone Microarchitecture Between Adult Osteogenesis Imperfecta and Early-Onset Osteoporosis

Diagnosis and management of adult individuals with low bone mass and increased bone fragility before the age of 50 can be challenging. A number of these patients are diagnosed with mild osteogenesis imperfecta (OI) through detection of COL1A1 or COL1A2 mutations; however, a clinical differentiation from early-onset osteoporosis (EOOP) may be difficult. The purpose of this study was to determine the bone microstructural differences between mild OI and EOOP patients. 29 patients showed mutations in COL1A1 or COL1A2 and were classified as OI. Skeletal assessment included dual-energy X-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HR-pQCT), and bone turnover serum analyses. Bone microstructure of 21/29 OI patients was assessed and compared to 23 age- and sex-matched patients clinically classified EOOP but without mutations in the known disease genes as well as to 20 healthy controls. In the OI patients, we did not observe an age-dependent decrease in DXA Z-scores. HR-pQCT revealed a significant reduction in volumetric BMD and microstructural parameters in the distal radius and tibia in both the OI and EOOP cohorts compared to the healthy controls. When comparing the bone microstructure of OI patients with the EOOP cohort, significant differences were found in terms of bone geometry in the radius, while no significant changes were detected in all other HR-pQCT parameters at the radius and tibia. Taken together, adult mild OI patients demonstrate a predominantly high bone turnover trabecular bone loss syndrome that shows minor microstructural differences compared to EOOP without mutation detection.

Trabecular bone microarchitecture predicts fragility fractures in postmenopausal women on denosumab treatment

BACKGROUND High-resolution peripheral quantitative computed tomography (HR-pQCT) represents a three-dimensional tool for the screening of osteoporosis patients i.e., regarding fracture risk. The purpose of this study was to determine the baseline and follow-up bone microarchitecture in relation to incident fracture risk in postmenopausal women on denosumab treatment. METHODS We have retrospectively evaluated data from 182 postmenopausal women treated with denosumab that underwent an initial HR-pQCT scan before the initiation of the treatment; and at least one second HR-pQCT after 12 months. Women were assigned to two groups based on documented fragility fractures for the following 2.9 ± 1.1 years: fracture (n = 22) and no fracture (n = 160). Baseline parameters from DXA, HR-pQCT and bone turnover were compared between the two groups. Furthermore, ROC and multiple regression analyses of the baseline and follow-up data were performed to evaluate the predictive value regarding incident fractures. RESULTS At baseline, trabecular parameters were significantly reduced in the fracture group and showed the best predictive value for new fractures, while DXA results could not predict fractures. A multiple regression model identified BV/TV and age as the best baseline parameters for incident fracture risk. At 12 months, cortical and trabecular parameters increased in the non-fracture group, while no significant increase was noted in the fracture group. However, no significant differences regarding the changes of these parameters could be detected between the non-fracture and fracture cohort. CONCLUSIONS Trabecular bone microstructure at baseline is crucial for incident fracture risk in postmenopausal women on denosumab treatment, especially in comparison to DXA values. In this context, the microstructural follow-up results seemed to be of lesser importance regarding fracture risk. The results of this exploratory study should be validated in independent populations.