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Featured researches published by Tim Rolvien.


Journal of Bone and Mineral Research | 2017

A Novel ANO5 Mutation Causing Gnathodiaphyseal Dysplasia with High Bone Turnover Osteosclerosis

Tim Rolvien; Till Koehne; Uwe Kornak; Wolfgang Lehmann; Michael Amling; Thorsten Schinke; Ralf Oheim

Gnathodiaphyseal dysplasia (GDD) is a rare skeletal syndrome that involves an osteopetrosis‐like sclerosis of the long bones and fibrous dysplasia–like cemento‐osseous lesions of the jawbone. Although the genetic analysis of the respective patients has revealed mutations in the ANO5 gene as an underlying cause, there is still no established consensus regarding the bone status of GDD patients. We report a new case of GDD in a 13‐year‐old boy with recurrent diaphyseal fractures of the femur, in whom we identified a novel de novo missense mutation in the ANO5 gene, causing a p.Ser500Phe substitution at the protein level. After confirming the presence of GDD‐characteristic abnormalities within the jaw bones, we focused on a full osteologic assessment using dual‐energy X‐ray absorptiometry (DXA), high‐resolution peripheral quantitative computed tomography (HR‐pQCT), and serum analyses. We thereby identified increased trabecular bone mass accompanied by elevated serum markers of bone formation and bone resorption. The high turnover bone pathology was further confirmed through the analysis of an iliac crest biopsy, where osteoblast and osteoclast indices were remarkably increased. Taken together, our findings provide evidence for a critical and generalized role of anoctamin‐5 (the protein encoded by the ANO5 gene) in skeletal biology. As it is reasonable to speculate that modifying the function of anoctamin‐5 might be useful for therapeutically activating bone remodeling, it is now required to analyze its function at a molecular level, for instance in mouse models.


American Journal of Sports Medicine | 2015

Intact Bone Vitality and Increased Accumulation of Nonmineralized Bone Matrix in Biopsy Specimens of Juvenile Osteochondritis Dissecans A Histological Analysis

Matthias Krause; Daniel Lehmann; Michael Amling; Tim Rolvien; Karl-Heinz Frosch; Klaus Püschel; Klaus Bohndorf; N. M. Meenen

Background: Although commonly proposed to be the starting point of juvenile osteochondritis dissecans (JOCD), avascular osteonecrosis (AVN) has been an inconsistent finding in histological studies. Analysis of early-stage lesions is required to elucidate the origins of OCD and justify proper treatment. Purpose: To analyze histological sections of JOCD lesions with special emphasis on bone vitality. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Of 64 patients with 74 JOCD lesions (20 females, mean age, 11.4 years; 44 males, mean age, 12.7 years), 34 required surgery because of lesion instability or failed nonoperative treatment. From 9 patients, 11 histological specimens were obtained. Lesions were classified according to the International Cartilage Repair Society (ICRS). Two additional histological control sections were harvested from children without JOCD manifestation. Undecalcified histological sections were histomorphometrically analyzed. To analyze the skeletal health of the patients, biochemical analyses with special emphasis on bone metabolism were performed. Results: Histologically, no osteonecrosis was visible in any of the cases. Osteocyte distribution was similar among OCD lesions and controls. ICRS OCD I lesions (n = 6) showed no intralesional separation. In ICRS OCD II and III lesions (n = 5), there was a subchondral fracture concomitant with histological characteristics of active repair mechanism (increased bone formation: osteoid volume P = .008, osteoblast number P = .046; resorption: osteoclast number P = .005; and tissue fibrosis compared with controls). Instead, in ICRS OCD I lesions, subchondral osteoid volume (P = .010) and osteoblast number (P = .046) were significantly increased compared with controls; however, no active repair mechanisms (no increased bone resorption or fibrous tissue) were detected, suggesting a focal lack of mineralization. Fifty-seven of 64 patients (89.1%) showed a vitamin D deficiency. The median vitamin D serum level of the patients with ICRS OCD I lesions was 13.6 µg/L. Conclusion: In the present study, osteonecrosis was not found in histological specimens of JOCD. As a secondary finding, focal accumulations of nonmineralized bone matrix indicating a lack of mineralization in ICRS OCD I lesions were revealed. This finding correlated with a low level of vitamin D in the affected children.


Osteoporosis International | 2017

Clinical, radiographic and biochemical characteristics of adult hypophosphatasia

Tobias Schmidt; Haider Mussawy; Tim Rolvien; Thelonius Hawellek; Jan Hubert; Wolfgang Rüther; Michael Amling; Florian Barvencik

SummaryIn this study, we report on clinical, radiographic and biochemical characteristics of 38 patients with adult hypophosphatasia. High-resolution peripheral quantitative computed tomography showed alterations of bone microstructure in a subgroup of 14 patients. Pyridoxal-5-phosphate levels correlated with the occurrence of fractures and the number of symptoms.IntroductionHypophosphatasia (HPP) is a rare disorder with a wide range of clinical manifestations. A reduced enzymatic activity of alkaline phosphatase (ALP) is the key marker of the disease, causing an accumulation of ALP substrates such as pyridoxal-5-phosphate (PLP). The purpose of this retrospective study was to further characterize adult onset HPP.MethodsWe assessed clinical, radiographic and laboratory characteristics of 38 adult patients with HPP. Diagnosis of HPP was established by the combination of low-serum ALP, raised PLP levels and typical symptoms and was genetically confirmed in 32 patients. Dual-energy X-ray absorptiometry (DXA) and laboratory data were available in most patients. High-resolution peripheral quantitative computed tomography (HR-pQCT) was performed in 14 patients.ResultsClinical characteristics included a wide spectrum of symptoms. A history of fracture was present in 15 patients (39%). Twenty-one patients (55%) complained about recurring headaches, 23 patients (61%) had recurring muscle pain, 4 patients (11%) suffered from severe muscle weakness and 18 patients (47%) showed dental abnormalities. Z-scores assessed by DXA were only slightly reduced in most adult HPP patients. HR-pQCT of 14 patients showed microstructural changes of trabecular and cortical bone compared to reference values of healthy subjects. The occurrence of fractures and multiple symptoms (>2 typical HPP symptoms) were associated with significantly elevated levels of PLP.ConclusionAdult HPP presents with a wide range of clinical symptoms and is not associated with low bone mass in general. PLP seems to be a good marker for disease severity in adult patients as its level is correlated with the occurrence of fractures and number of symptoms.


Bone | 2017

Vitamin D regulates osteocyte survival and perilacunar remodeling in human and murine bone

Tim Rolvien; Matthias Krause; Anke Jeschke; Timur Yorgan; Klaus Püschel; Thorsten Schinke; Marie B. Demay; Michael Amling

Osteocytes are the most abundant bone cells and are highly regulated by external stimuli. Vitamin D and osteocytes cooperatively regulate bone remodeling as well as phosphate and calcium homeostasis. However, it is unclear if vitamin D regulates osteocyte number, connectivity or size in the setting of altered bone formation or impaired mineralization. Sixty iliac crest biopsies of patients with varying vitamin D levels were examined to analyze osteocyte number, osteocyte connectivity and osteocyte viability using high-resolution imaging. Osteocyte parameters were also quantified in mice lacking the vitamin D receptor (Vdr-/-) and in wildtype littermates. The cortical and cancellous bone of patients with vitamin D deficiency exhibited a significant decrease in the number of viable osteocytes, as well as increased osteocyte apoptosis and impaired osteocyte connectivity, based on evaluation of the canalicular network. The number of osteocytes was also decreased in Vdr-deficient mice, in comparison to wildtype controls, and this was accompanied by enlargement of osteocyte lacunae. A high calcium diet normalized the osteocyte lacunar area in Vdr-deficient mice, but failed to normalize osteocyte number. Thus, a diet-independent decrease in osteocyte number in Vdr-deficient mice suggests a mechanism that is directly dependent on the VDR, since vitamin D may promote the transition from osteoblasts to osteocytes. The increase in lacunar area the in Vdr-deficient mice, which is normalized by the high calcium diet suggests this phenotype is due to osteocytic osteolysis. These investigations demonstrate that vitamin D plays a role in the regulation of osteocyte number and perilacunar remodeling.


Injury-international Journal of The Care of The Injured | 2017

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

Tim Rolvien; Tobias Schmidt; Sebastian Butscheidt; Michael Amling; Florian Barvencik

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.


Scientific Reports | 2018

Increased mechanical loading through controlled swimming exercise induces bone formation and mineralization in adult zebrafish

Santiago Suniaga; Tim Rolvien; Annika vom Scheidt; Imke Astrid Kristina Fiedler; Hrishikesh Bale; Ann Huysseune; P. Eckhard Witten; Michael Amling

Exercise promotes gain in bone mass through adaptive responses of the vertebrate skeleton. This mechanism counteracts age- and disease-related skeletal degradation, but remains to be fully understood. In life sciences, zebrafish emerged as a vertebrate model that can provide new insights into the complex mechanisms governing bone quality. To test the hypothesis that musculoskeletal exercise induces bone adaptation in adult zebrafish and to characterize bone reorganization, animals were subjected to increased physical exercise for four weeks in a swim tunnel experiment. Cellular, structural and compositional changes of loaded vertebrae were quantified using integrated high-resolution analyses. Exercise triggered rapid bone adaptation with substantial increases in bone-forming osteoblasts, bone volume and mineralization. Clearly, modeling processes in zebrafish bone resemble processes in human bone. This study highlights how exercise experiments in adult zebrafish foster in-depth insight into aging-related bone diseases and can thus catalyze the search for appropriate prevention and new treatment options.


Journal of Bone and Mineral Research | 2018

High bone turnover in mice carrying a pathogenic Notch2-mutation causing Hajdu-Cheney syndrome†

Nele Vollersen; Irm Hermans-Borgmeyer; Kerstin Cornils; Boris Fehse; Tim Rolvien; Ioanna Triviai; Anke Jeschke; Ralf Oheim; Michael Amling; Thorsten Schinke; Timur Yorgan

Hajdu‐Cheney syndrome (HCS) is a rare autosomal‐dominant disorder primarily characterized by acro‐osteolysis and early‐onset osteoporosis. Genetically, HCS is caused by nonsense or deletion mutations within exon 34 of the NOTCH2 gene, resulting in premature translational termination and production of C‐terminally truncated NOTCH2 proteins that are predicted to activate NOTCH2‐dependent signaling. To understand the role of Notch2 in bone remodeling, we developed a mouse model of HCS by introducing a pathogenic mutation (6272delT) into the murine Notch2 gene. By μCT and undecalcified histology, we observed generalized osteopenia in two independent mouse lines derived by injection of different targeted embryonic stem (ES) cell clones, yet acro‐osteolysis did not occur until the age of 52 weeks. Cellular and dynamic histomorphometry revealed a high bone turnover situation in Notch2+/HCS mice, since osteoblast and osteoclast indices were significantly increased compared with wild‐type littermates. Whereas ex vivo cultures failed to uncover cell‐autonomous gain‐of‐functions within the osteoclast or osteoblast lineage, an unbiased RNA sequencing approach identified Tnfsf11 and Il6 as Notch‐signaling target genes in bone marrow cells cultured under osteogenic conditions. Because we further observed that the high‐turnover pathology of Notch2+/HCS mice was fully normalized by alendronate treatment, our results demonstrate that mutational activation of Notch2 does not directly control osteoblast activity but favors a pro‐osteoclastic gene expression pattern, which in turn triggers high bone turnover.


Injury-international Journal of The Care of The Injured | 2017

Changes in cortical microarchitecture are independent of areal bone mineral density in patients with fragility fractures

Haider Mussawy; Gero Ferrari; Felix Schmidt; Tobias Schmidt; Tim Rolvien; Sandra Hischke; Wolfgang Rüther; Michael Amling

Dual-energy X-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT) are commonly used to assess the areal bone mineral density (aBMD) and peripheral microstructure, respectively. While DXA is the standard to diagnose osteoporosis, HR-pQCT provides information about the cortical and trabecular architecture. Many fragility fractures occur in patients who do not meet the osteoporosis criterion (i.e., T-score≤-2.5). We hypothesize that patients with T-score above -2.5 and fragility fracture may have abnormal bone microarchitecture. Therefore, in this retrospective clinical study, HR-pQCT data obtained from patients with fragility fractures and T-scores≥-2.5 (n=71) were compared to corresponding data from patients with fragility fractures and T-scores≤-3.5 (n=56). Types of secondary osteoporosis were excluded from the study. To verify the dependency of alterations in bone microarchitecture and T-score, the association between HR-pQCT values and aBMD as reflected by the T-score at both proximal femora, was assessed. At the distal tibia, cortical thickness was lower (p<0.001), cortical porosity was similar (p=0.61), trabecular number was higher (p<0.001), and bone volume fraction (BV/TV) was higher (p<0.001) in patients with T-scores≥-2.5 than in patients with T-scores≤-3.5. Trabecular number and BV/TV correlated with T-score (r=0.68, p<0.001; r=0.61, p<0.001), whereas the cortical values did not. Our results thus demonstrate the importance of bone structure, as assessed by HR-pQCT, in addition to the standard DXA T-score in the diagnosis of osteoporosis.


Journal of Bone and Mineral Research | 2018

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

Tobias Schmidt; Constantin Schmidt; Felix Schmidt; Sebastian Butscheidt; Haider Mussawy; Jan Hubert; Thelonius Hawellek; Nicola Oehler; Florian Barvencik; Ansgar W. Lohse; Thorsten Schinke; Christoph Schramm; Michael Amling; Tim Rolvien

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.


Scientific Reports | 2017

Vertebral bone microarchitecture and osteocyte characteristics of three toothed whale species with varying diving behaviour

Tim Rolvien; Michael Hahn; Ursula Siebert; Klaus Püschel; Hans-Joachim Wilke; Michael Amling; Ralf Oheim

Although vertebral bone microarchitecture has been studied in various tetrapods, limited quantitative data are available on the structural and compositional changes of vertebrae in marine mammals. Whales exhibit exceptional swimming and diving behaviour, and they may not be immune to diving-associated bone pathologies. Lumbar vertebral bodies were analysed in three toothed whale species: the sperm whale (Physeter macrocephalus), orca (Orcinus orca) and harbour porpoise (Phocoena phocoena). The bone volume fraction (BV/TV) did not scale with body size, although the trabeculae were thicker, fewer in number and further apart in larger whale species than in the other two species. These parameters had a negative allometric scaling relationship with body length. In sperm whales and orcas, the analyses revealed a central ossification zone (“bone-within-bone”) with an increased BV/TV and trabecular thickness. Furthermore, a large number of empty osteocyte lacunae was observed in the sperm whales. Quantitative backscattered electron imaging showed that the lacunae were significantly smaller and less densely packed. Our results indicate that whales have a unique vertebral bone morphology with an inside-out appearance and that deep diving may result in a small number of viable osteocytes because of diving depth-related osteocyte death.

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