@article{ModicaAltieriD’Anielloetal.2023, author = {Modica, Roberta and Altieri, Barbara and D'Aniello, Francesco and Benevento, Elio and Cannavale, Giuseppe and Minotta, Roberto and Liccardi, Alessia and Colao, Annamaria and Faggiano, Antongiulio}, title = {Vitamin D and bone metabolism in adult patients with neurofibromatosis type 1}, series = {Metabolites}, volume = {13}, journal = {Metabolites}, number = {2}, issn = {2218-1989}, doi = {10.3390/metabo13020255}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-303957}, year = {2023}, abstract = {Neurofibromatosis type 1 (NF1) is a genetic multisystemic autosomal dominant disorder determining reduced life expectancy due to higher risk of developing benign and malignant tumors. Low levels of vitamin D and reduced bone mineral density (BMD) have been reported in young patients with NF1. However, correlation between vitamin D and NF1 phenotype needs to be elucidated. Aim of this study was to assess vitamin D levels and bone metabolism in NF1 patients, analyzing potential correlations with clinical phenotype. A cross-sectional study was carried out in a monocentric series of NF1 patients, evaluating genotype, clinical phenotype, BMD, biochemical evaluation with focus on serum 25OH-vitamin D, parathyroid hormone (PTH), calcium and phosphate levels. Correlations between clinical manifestations, neurofibromas, and vitamin D status have been studied in comparison with healthy controls. 31 NF1 adult patients were matched for sex, age and body mass index with 31 healthy controls. A significantly difference in vitamin D level emerged in NF1 patients compared to controls. Interestingly low vitamin D levels correlated with a more aggressive phenotype and with a bigger size of neurofibromas. These data underline that vitamin D deficiency/insufficiency may play a role in clinical severity of neurofibromas in patients with NF1, suggesting the need to check bone status and replace vitamin D in these patients.}, language = {en} } @article{StratosRinasSchroepferetal.2023, author = {Stratos, Ioannis and Rinas, Ingmar and Schr{\"o}pfer, Konrad and Hink, Katharina and Herlyn, Philipp and B{\"a}umler, Mario and Histing, Tina and Bruhn, Sven and M{\"u}ller-Hilke, Brigitte and Menger, Michael D. and Vollmar, Brigitte and Mittlmeier, Thomas}, title = {Effects on bone and muscle upon treadmill interval training in hypogonadal male rats}, series = {Biomedicines}, volume = {11}, journal = {Biomedicines}, number = {5}, issn = {2227-9059}, doi = {10.3390/biomedicines11051370}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-319266}, year = {2023}, abstract = {Testosterone deficiency in males is linked to various pathological conditions, including muscle and bone loss. This study evaluated the potential of different training modalities to counteract these losses in hypogonadal male rats. A total of 54 male Wistar rats underwent either castration (ORX, n = 18) or sham castration (n = 18), with 18 castrated rats engaging in uphill, level, or downhill interval treadmill training. Analyses were conducted at 4, 8, and 12 weeks postsurgery. Muscle force of the soleus muscle, muscle tissue samples, and bone characteristics were analyzed. No significant differences were observed in cortical bone characteristics. Castrated rats experienced decreased trabecular bone mineral density compared to sham-operated rats. However, 12 weeks of training increased trabecular bone mineral density, with no significant differences among groups. Muscle force measurements revealed decreased tetanic force in castrated rats at week 12, while uphill and downhill interval training restored force to sham group levels and led to muscle hypertrophy compared to ORX animals. Linear regression analyses showed a positive correlation between bone biomechanical characteristics and muscle force. The findings suggest that running exercise can prevent bone loss in osteoporosis, with similar bone restoration effects observed across different training modalities.}, language = {en} } @article{SeefriedGenestBaumannetal.2022, author = {Seefried, Lothar and Genest, Franca and Baumann, Jasmin and Heidemeier, Anke and Meffert, Rainer and Jakob, Franz}, title = {Efficacy of Zoledronic Acid in the Treatment of Nonmalignant Painful Bone Marrow Lesions: A Triple-Blind, Randomized, Placebo-Controlled Phase III Clinical Trial (ZoMARS)}, series = {Journal of Bone and Mineral Research}, volume = {37}, journal = {Journal of Bone and Mineral Research}, number = {3}, doi = {10.1002/jbmr.4493}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-276368}, pages = {420 -- 427}, year = {2022}, abstract = {Bone marrow lesions (BML) represent areas of deteriorated bone structure and metabolism characterized by pronounced water-equivalent signaling within the trabecular bone on magnetic resonance imaging (MRI). BML are associated with repair mechanisms subsequent to various clinical conditions associated with inflammatory and non-inflammatory injury to the bone. There is no approved treatment for this condition. Bisphosphonates are known to improve bone stability in osteoporosis and other bone disorders and have been used off-label to treat BML. A randomized, triple-blind, placebo-controlled phase III trial was conducted to assess efficacy and safety of single-dose zoledronic acid (ZOL) 5 mg iv with vitamin D 1000 IU/d as opposed to placebo with vitamin D 1000 IU/d in 48 patients (randomized 2:1) with BML. Primary efficacy endpoint was reduction of edema volume 6 weeks after treatment as assessed by MRI. After treatment, mean BML volume decreased by 64.53\% (±41.92\%) in patients receiving zoledronic acid and increased by 14.43\% (±150.46\%) in the placebo group (p = 0.007). A decrease in BML volume was observed in 76.5\% of patients receiving ZOL and in 50\% of the patients receiving placebo. Pain level (visual analogue scale [VAS]) and all categories of the pain disability index (PDI) improved with ZOL versus placebo after 6 weeks but reconciled after 6 additional weeks of follow-up. Six serious adverse events occurred in 5 patients, none of which were classified as related to the study drug. No cases of osteonecrosis or fractures occurred. Therefore, single-dose zoledronic acid 5 mg iv together with vitamin D may enhance resolution of bone marrow lesions over 6 weeks along with reduction of pain compared with vitamin D supplementation only.}, language = {en} } @article{AltieriDiDatoModicaetal.2020, author = {Altieri, Barbara and Di Dato, Carla and Modica, Roberta and Bottiglieri, Filomena and Di Sarno, Antonella and Pittaway, James F.H. and Martini, Chiara and Faggiano, Antongiulio and Colao, Annamaria}, title = {Bone metabolism and vitamin D implication in gastroenteropancreatic neuroendocrine tumors}, series = {Nutrients}, volume = {12}, journal = {Nutrients}, number = {4}, issn = {2072-6643}, doi = {10.3390/nu12041021}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-203823}, year = {2020}, abstract = {Patients affected by gastroenteropancreatic-neuroendocrine tumors (GEP-NETs) have an increased risk of developing osteopenia and osteoporosis, as several factors impact on bone metabolism in these patients. In fact, besides the direct effect of bone metastasis, bone health can be affected by hormone hypersecretion (including serotonin, cortisol, and parathyroid hormone-related protein), specific microRNAs, nutritional status (which in turn could be affected by medical and surgical treatments), and vitamin D deficiency. In patients with multiple endocrine neoplasia type 1 (MEN1), a hereditary syndrome associated with NET occurrence, bone damage may carry other consequences. Osteoporosis may negatively impact on the quality of life of these patients and can increment the cost of medical care since these patients usually live with their disease for a long time. However, recommendations suggesting screening to assess bone health in GEP-NET patients are missing. The aim of this review is to critically analyze evidence on the mechanisms that could have a potential impact on bone health in patients affected by GEP-NET, focusing on vitamin D and its role in GEP-NET, as well as on factors associated with MEN1 that could have an impact on bone homeostasis.}, language = {en} } @article{NiedermairLukasLietal.2020, author = {Niedermair, Tanja and Lukas, Christoph and Li, Shushan and St{\"o}ckl, Sabine and Craiovan, Benjamin and Brochhausen, Christoph and Federlin, Marianne and Herrmann, Marietta and Gr{\"a}ssel, Susanne}, title = {Influence of Extracellular Vesicles Isolated From Osteoblasts of Patients With Cox-Arthrosis and/or Osteoporosis on Metabolism and Osteogenic Differentiation of BMSCs}, series = {Frontiers in Bioengineering and Biotechnology}, volume = {8}, journal = {Frontiers in Bioengineering and Biotechnology}, issn = {2296-4185}, doi = {10.3389/fbioe.2020.615520}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-219902}, year = {2020}, abstract = {Background: Studies with extracellular vesicles (EVs), including exosomes, isolated from mesenchymal stem cells (MSC) indicate benefits for the treatment of musculoskeletal pathologies as osteoarthritis (OA) and osteoporosis (OP). However, little is known about intercellular effects of EVs derived from pathologically altered cells that might influence the outcome by counteracting effects from "healthy" MSC derived EVs. We hypothesize, that EVs isolated from osteoblasts of patients with hip OA (coxarthrosis/CA), osteoporosis (OP), or a combination of both (CA/OP) might negatively affect metabolism and osteogenic differentiation of bone-marrow derived (B)MSCs. Methods: Osteoblasts, isolated from bone explants of CA, OP, and CA/OP patients, were compared regarding growth, viability, and osteogenic differentiation capacity. Structural features of bone explants were analyzed via μCT. EVs were isolated from supernatant of na{\"i}ve BMSCs and CA, OP, and CA/OP osteoblasts (osteogenic culture for 35 days). BMSC cultures were stimulated with EVs and subsequently, cell metabolism, osteogenic marker gene expression, and osteogenic differentiation were analyzed. Results: Trabecular bone structure was different between the three groups with lowest number and highest separation in the CA/OP group. Viability and Alizarin red staining increased over culture time in CA/OP osteoblasts whereas growth of osteoblasts was comparable. Alizarin red staining was by trend higher in CA compared to OP osteoblasts after 35 days and ALP activity was higher after 28 and 35 days. Stimulation of BMSC cultures with CA, OP, and CA/OP EVs did not affect proliferation but increased caspase 3/7-activity compared to unstimulated BMSCs. BMSC viability was reduced after stimulation with CA and CA/OP EVs compared to unstimulated BMSCs or stimulation with OP EVs. ALP gene expression and activity were reduced in BMSCs after stimulation with CA, OP, and CA/OP EVs. Stimulation of BMSCs with CA EVs reduced Alizarin Red staining by trend. Conclusion: Stimulation of BMSCs with EVs isolated from CA, OP, and CA/OP osteoblasts had mostly catabolic effects on cell metabolism and osteogenic differentiation irrespective of donor pathology and reflect the impact of tissue microenvironment on cell metabolism. These catabolic effects are important for understanding differences in effects of EVs on target tissues/cells when harnessing them as therapeutic drugs.}, language = {en} } @article{GenestRakBaetzetal.2021, author = {Genest, Franca and Rak, Dominik and B{\"a}tz, Elisa and Ott, Kerstin and Seefried, Lothar}, title = {Sarcopenia and Malnutrition Screening in Female Osteoporosis Patients — A Cross-Sectional Study}, series = {Journal of Clinical Medicine}, volume = {10}, journal = {Journal of Clinical Medicine}, number = {11}, issn = {2077-0383}, doi = {10.3390/jcm10112344}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239658}, year = {2021}, abstract = {Sarcopenia and malnutrition are important determinants of increased fracture risk in osteoporosis. SARC-F and MNA-SF are well-established questionnaires for identifying patients at risk for these conditions. We sought to evaluate the feasibility and potential added benefit of such assessments as well as the actual prevalence of these conditions in osteoporosis patients. We conducted a cross-sectional, single-center study in female osteoporosis patients ≥ 65 years (SaNSiBaR-study). Results of the sarcopenia (SARC-F) and malnutrition (MNA-SF) screening questionnaires were matched with a functional assessment for sarcopenia and data from patients' medical records. Out of 107 patients included in the analysis, a risk for sarcopenia (SARC-F ≥ 4 points) and a risk for malnutrition (MNA-SF ≤ 11 points) was found in 33 (30.8\%) and 38 (35.5\%) patients, respectively. Diagnostic overlap with coincident indicative findings in both questionnaires was observed in 17 patients (16\%). As compared to the respective not-at-risk groups, the mean short physical performance battery (SPPB) score was significantly reduced in both patients at risk for sarcopenia (7.0 vs. 10.9 points, p < 0.001) and patients at risk for malnutrition (8.7 vs. 10.5 points, p = 0.005). Still, confirmed sarcopenia according to EWGSOP2 criteria was present in only 6 (6\%) of all 107 patients, with only 3 of them having an indicative SARC-F score. Bone mineral density was not significantly different in any of the at-risk groups at any site. In summary, applying SARC-F and MNA-SF in osteoporosis patients appears to be a complementary approach to identify individuals with functional deficits.}, language = {en} } @article{GenestClaussenRaketal.2021, author = {Genest, F. and Claußen, L. and Rak, D. and Seefried, L.}, title = {Bone mineral density and fracture risk in adult patients with hypophosphatasia}, series = {Osteoporosis International}, volume = {32}, journal = {Osteoporosis International}, issn = {0937-941X}, doi = {10.1007/s00198-020-05612-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-235793}, pages = {377-385}, year = {2021}, abstract = {Summary In adult hypophosphatasia (HPP) patients, elevated lumbar spine dual X-ray absorptiometry (DXA) values are associated with markers of disease severity and disease-specific fracture risk while femoral bone mineral density (BMD), being largely unaffected by the disease severity, may still be useful to monitor other causes of increased fracture risk due to low BMD. Introduction Hypophosphatasia (HPP) is a rare inherited metabolic disorder due to deficient activity of the tissue-nonspecific alkaline phosphatase (TNAP). Clinical manifestation in adult HPP patients is manifold including an increased risk for fractures, but data regarding clinical significance of DXA measurement and associations with fracture risk and disease severity is scarce. Methods Retrospective single-center analysis of DXA scans in patients with confirmed HPP (documented mutation, clinical symptoms, low alkaline phosphatase activity). Further data evaluation included disease-related fractures, laboratory results (alkaline phosphatase, pyridoxalphosphate, phosphoethanolamine), and medical history. Results Analysis included 110 patients (84 female, mean age of 46.2 years) of whom 37.3\% (n = 41) were harboring two mutations. Average T-Score level at the lumbar spine was - 0.1 (SD 1.9), and mean total hip T-Score was - 1.07 (SD 0.15). Both lower ALP activity and higher substrate levels (pyridoxalphosphate and phosphoethanolamine) were significantly correlated with increased lumbar spine T-Score levels (p < 0.001) while BMD at the hip was not affected by indicators of disease severity. Increased lumbar spine BMD was significantly associated with an increased risk for HPP-related fractures, prevalent in 22 (20\%) patients (p < 0.001) with 21 of them having biallelic mutations. Conclusion BMD in adult HPP patients is not systematically reduced. Conversely, increased lumbar spine BMD appears to be associated with severely compromised mineralization and increased risk for HPP-related fractures while BMD at the hip appears unaffected by indicators of disease severity, suggesting suitability of this anatomic location for assessing and discerning disorders with increased fracture risk owing to reduced BMD like osteoporosis. Trial registration number German register for clinical studies (DRKS00014022) Date of registration 02/10/2018 - retrospectively registered}, language = {en} } @article{KemmlerKohlFroehlichetal.2020, author = {Kemmler, Wolfgang and Kohl, Matthias and Fr{\"o}hlich, Michael and Jakob, Franz and Engelke, Klaus and von Stengel, Simon and Schoene, Daniel}, title = {Effects of High-Intensity Resistance Training on Osteopenia and Sarcopenia Parameters in Older Men with Osteosarcopenia—One-Year Results of the Randomized Controlled Franconian Osteopenia and Sarcopenia Trial (FrOST)}, series = {Journal of Bone and Mineral Research}, volume = {35}, journal = {Journal of Bone and Mineral Research}, number = {9}, doi = {10.1002/jbmr.4027}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-214609}, pages = {1634 -- 1644}, year = {2020}, abstract = {Dynamic resistance exercise (DRT) might be the most promising agent for fighting sarcopenia in older people. However, the positive effect of DRT on osteopenia/osteoporosis in men has still to be confirmed. To evaluate the effect of low-volume/high-intensity (HIT)-DRT on bone mineral density (BMD) and skeletal muscle mass index (SMI) in men with osteosarcopenia, we initiated the Franconian Osteopenia and Sarcopenia Trial (FrOST). Forty-three sedentary community-dwelling older men (aged 73 to 91 years) with osteopenia/osteoporosis and SMI-based sarcopenia were randomly assigned to a HIT-RT exercise group (EG; n = 21) or a control group (CG; n = 22). HIT-RT provided a progressive, periodized single-set DRT on machines with high intensity, effort, and velocity twice a week, while CG maintained their lifestyle. Both groups were adequately supplemented with whey protein, vitamin D, and calcium. Primary study endpoint was integral lumbar spine (LS) BMD as determined by quantitative computed tomography. Core secondary study endpoint was SMI as determined by dual-energy X-ray absorptiometry. Additional study endpoints were BMD at the total hip and maximum isokinetic hip-/leg-extensor strength (leg press). After 12 months of exercise, LS-BMD was maintained in the EG and decreased significantly in the CG, resulting in significant between-group differences (p < 0.001; standardized mean difference [SMD] = 0.90). In parallel, SMI increased significantly in the EG and decreased significantly in the CG (p < 0.001; SMD = 1.95). Total hip BMD changes did not differ significantly between the groups (p = 0.064; SMD = 0.65), whereas changes in maximum hip-/leg-extensor strength were much more prominent (p < 0.001; SMD = 1.92) in the EG. Considering dropout (n = 2), attendance rate (95\%), and unintended side effects/injuries (n = 0), we believe our HIT-RT protocol to be feasible, attractive, and safe. In summary, we conclude that our combined low-threshold HIT-RT/protein/vitamin D/calcium intervention was feasible, safe, and effective for tackling sarcopenia and osteopenia/osteoporosis in older men with osteosarcopenia.}, language = {en} } @article{FuchsHeiligMcDonoghetal.2020, author = {Fuchs, Konrad F. and Heilig, Philipp and McDonogh, Miriam and Boelch, Sebastian and Gbureck, Uwe and Meffert, Rainer H. and Hoelscher-Doht, Stefanie and Jordan, Martin C.}, title = {Cement-augmented screw fixation for calcaneal fracture treatment: a biomechanical study comparing two injectable bone substitutes}, series = {Journal of Orthopaedic Surgery and Research}, volume = {15}, journal = {Journal of Orthopaedic Surgery and Research}, doi = {10.1186/s13018-020-02009-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230336}, year = {2020}, abstract = {Background The role of cement-augmented screw fixation for calcaneal fracture treatment remains unclear. Therefore, this study was performed to biomechanically analyze screw osteosynthesis by reinforcement with either a calcium phosphate (CP)-based or polymethylmethacrylate (PMMA)-based injectable bone cement. Methods A calcaneal fracture (Sanders type IIA) including a central cancellous bone defect was generated in 27 synthetic bones, and the specimens were assigned to 3 groups. The first group was fixed with four screws (3.5 mm and 6.5 mm), the second group with screws and CP-based cement (Graftys (R) QuickSet; Graftys, Aix-en-Provence, France), and the third group with screws and PMMA-based cement (Traumacem (TM) V+; DePuy Synthes, Warsaw, IN, USA). Biomechanical testing was conducted to analyze peak-to-peak displacement, total displacement, and stiffness in following a standardized protocol. Results The peak-to-peak displacement under a 200-N load was not significantly different among the groups; however, peak-to-peak displacement under a 600- and 1000-N load as well as total displacement exhibited better stability in PMMA-augmented screw osteosynthesis compared to screw fixation without augmentation. The stiffness of the construct was increased by both CP- and PMMA-based cements. Conclusion Addition of an injectable bone cement to screw osteosynthesis is able to increase fixation strength in a biomechanical calcaneal fracture model with synthetic bones. In such cases, PMMA-based cements are more effective than CP-based cements because of their inherently higher compressive strength. However, whether this high strength is required in the clinical setting for early weight-bearing remains controversial, and the non-degradable properties of PMMA might cause difficulties during subsequent interventions in younger patients.}, language = {en} } @article{BoschertFrischBacketal.2016, author = {Boschert, V. and Frisch, C. and Back, J. W. and van Pee,, K. and Weidauer, S. E. and Muth, E.-M. and Schmieder, P. and Beerbaum, M. and Knappik, A. and Timmerman, P. and Mueller, T. D.}, title = {The sclerostin-neutralizing antibody AbD09097 recognizes an epitope adjacent to sclerostin's binding site for the Wnt co-receptor LRP6}, series = {Open Biology}, volume = {6}, journal = {Open Biology}, doi = {10.1098/rsob.160120}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177925}, year = {2016}, abstract = {The glycoprotein sclerostin has been identified as a negative regulator of bone growth. It exerts its function by interacting with the Wnt co-receptor LRP5/6, blocks the binding of Wnt factors and thereby inhibits Wnt signalling. Neutralizing anti-sclerostin antibodies are able to restore Wnt activity and enhance bone growth thereby presenting a new osteoanabolic therapy approach for diseases such as osteoporosis. We have generated various Fab antibodies against human and murine sclerostin using a phage display set-up. Biochemical analyses have identified one Fab developed against murine sclerostin, AbD09097 that efficiently neutralizes sclerostin's Wnt inhibitory activity. In vitro interaction analysis using sclerostin variants revealed that this neutralizing Fab binds to sclerostin's flexible second loop, which has been shown to harbour the LRP5/6 binding motif. Affinity maturation was then applied to AbD09097, providing a set of improved neutralizing Fab antibodies which particularly bind human sclerostin with enhanced affinity. Determining the crystal structure of AbD09097 provides first insights into how this antibody might recognize and neutralize sclerostin. Together with the structure-function relationship derived from affinity maturation these new data will foster the rational design of new and highly efficient anti-sclerostin antibodies for the therapy of bone loss diseases such as osteoporosis.}, language = {en} }