nach oben

Current Osteoporosis Reports

Erschienen in:

16.09.2019 | Cancer-induced Musculoskeletal Diseases (E Keller and J Sterling, Section editors)

Osteosarcoma in the Post Genome Era: Preclinical Models and Approaches to Identify Tractable Therapeutic Targets

verfasst von: Wilson Castillo-Tandazo, Anthony J. Mutsaers, Carl R. Walkley

Erschienen in: Current Osteoporosis Reports | Ausgabe 5/2019

Einloggen, um Zugang zu erhalten

Abstract

Purpose of Review

Osteosarcoma (OS) is the most common cancer of bone, yet is classified as a rare cancer. Treatment and outcomes for OS have not substantively changed in several decades. While the decoding of the OS genome greatly advanced the understanding of the mutational landscape of OS, immediately actionable therapeutic targets were not apparent. Here we describe recent preclinical models that can be leveraged to identify, test, and prioritize therapeutic candidates.

Recent Findings

The generation of multiple high fidelity murine models of OS, the spontaneous disease that arises in pet dogs, and the establishment of a diverse collection of patient-derived OS xenografts provide a robust preclinical platform for OS. These models enable evidence to be accumulated across multiple stages of preclinical evaluation. Chemical and genetic screening has identified therapeutic targets, often demonstrating cross species activity. Clinical trials in both PDX models and in canine OS have effectively tested new therapies for prioritization.

Summary

Improving clinical outcomes in OS has proven elusive. The integrated target discovery and testing possible through a cross species platform provides validation of a putative target and may enable the rigorous evaluation of new therapies in models where endpoints can be rapidly assessed.

Ottaviani G, Jaffe N. The epidemiology of osteosarcoma. Cancer Treat Res. 2009;152:3–13.PubMed

Klein MJ, Siegal GP. Osteosarcoma: anatomic and histologic variants. Am J Clin Pathol. 2006;125(4):555–81.PubMed

Kansara M, Teng MW, Smyth MJ, Thomas DM. Translational biology of osteosarcoma. Nat Rev Cancer. 2014;14(11):722–35.PubMed

Janeway KA, Barkauskas DA, Krailo MD, Meyers PA, Schwartz CL, Ebb DH, et al. Outcome for adolescent and young adult patients with osteosarcoma: a report from the Children’s Oncology Group. Cancer. 2012;118(18):4597–605.PubMed

Bielack SS, Hecker-Nolting S, Blattmann C, Kager L. Advances in the management of osteosarcoma. F1000Res. 2016;5:2767.PubMedPubMedCentral

Perry JA, Kiezun A, Tonzi P, Van Allen EM, Carter SL, Baca SC, et al. Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma. Proc Natl Acad Sci U S A. 2014;111(51):E5564–73.PubMedPubMedCentral

Gupte A, Baker EK, Wan SS, Stewart E, Loh A, Shelat AA, et al. Systematic screening identifies dual PI3K and mTOR inhibition as a conserved therapeutic vulnerability in osteosarcoma. Clin Cancer Res. 2015;21(14):3216–29.PubMedPubMedCentral

Lamoureux F, Baud'huin M, Rodriguez Calleja L, Jacques C, Berreur M, Redini F, et al. Selective inhibition of BET bromodomain epigenetic signalling interferes with the bone-associated tumour vicious cycle. Nat Commun. 2014;5:3511.PubMed

Baker EK, Taylor S, Gupte A, Sharp PP, Walia M, Walsh NC, et al. BET inhibitors induce apoptosis through a MYC independent mechanism and synergise with CDK inhibitors to kill osteosarcoma cells. Sci Rep. 2015;5:10120.

10.

• Shekhar TM, Miles MA, Gupte A, Taylor S, Tascone B, Walkley CR, et al. IAP antagonists sensitize murine osteosarcoma cells to killing by TNFalpha. Oncotarget. 2016;7(23):33866–86. Demonstrated that OS cells are sensitive to non-genotosic agents such as SMAC mimetics.PubMedPubMedCentral

11.

•• Loh AHP, Stewart E, Bradley CL, Chen X, Daryani V, Stewart CF, et al. Combinatorial screening using orthotopic patient derived xenograft-expanded early phase cultures of osteosarcoma identify novel therapeutic drug combinations. Cancer Lett. 2019;442:262–70. A “clinical trial” using human primary OS PDXs. Demonstrated efficacy of novel therapeutic combinations.PubMed

12.

Cain JE, McCaw A, Jayasekara WS, Rossello FJ, Marini KD, Irving AT, et al. Sustained low-dose treatment with the histone deacetylase inhibitor LBH589 induces terminal differentiation of osteosarcoma cells. Sarcoma. 2013;2013:608964.PubMedPubMedCentral

13.

Mason NJ, Gnanandarajah JS, Engiles JB, Gray F, Laughlin D, Gaurnier-Hausser A, et al. Immunotherapy with a HER2-targeting Listeria induces HER2-specific immunity and demonstrates potential therapeutic effects in a phase I trial in canine osteosarcoma. Clin Cancer Res. 2016;22(17):4380–90.PubMed

14.

Fritz SE, Henson MS, Greengard E, Winter AL, Stuebner KM, Yoon U, et al. A phase I clinical study to evaluate safety of orally administered, genetically engineered Salmonella enterica serovar Typhimurium for canine osteosarcoma. Vet Med Sci. 2016;2(3):179–90.PubMedPubMedCentral

15.

Modiano JF, Bellgrau D, Cutter GR, Lana SE, Ehrhart NP, Ehrhart E, et al. Inflammation, apoptosis, and necrosis induced by neoadjuvant fas ligand gene therapy improves survival of dogs with spontaneous bone cancer. Mol Ther. 2012;20(12):2234–43.PubMedPubMedCentral

16.

Naik S, Galyon GD, Jenks NJ, Steele MB, Miller AC, Allstadt SD, et al. Comparative oncology evaluation of intravenous recombinant oncolytic vesicular stomatitis virus therapy in spontaneous canine Cancer. Mol Cancer Ther. 2018;17(1):316–26.PubMedPubMedCentral

17.

Chen X, Bahrami A, Pappo A, Easton J, Dalton J, Hedlund E, et al. Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma. Cell Rep. 2014;7(1):104–12.PubMed

18.

•• Behjati S, Tarpey PS, Haase K, Ye H, Young MD, Alexandrov LB, et al. Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma. Nat Commun. 2017;8:15936. Detailed analysis of the genomic landscape of > 100 human OS demonstrates distinct rearrangement types and a recurrent process characterized by chromothripsis and genomic amplification.PubMedPubMedCentral

19.

Lorenz S, Baroy T, Sun J, Nome T, Vodak D, Bryne JC, et al. Unscrambling the genomic chaos of osteosarcoma reveals extensive transcript fusion, recurrent rearrangements and frequent novel TP53 aberrations. Oncotarget. 2016;7(5):5273–88.PubMed

20.

Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ, et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell. 2011;144(1):27–40.PubMedPubMedCentral

21.

Kovac M, Blattmann C, Ribi S, Smida J, Mueller NS, Engert F, et al. Exome sequencing of osteosarcoma reveals mutation signatures reminiscent of BRCA deficiency. Nat Commun. 2015;6:8940.

22.

Mirabello L, Yeager M, Mai PL, Gastier-Foster JM, Gorlick R, Khanna C, et al. Germline TP53 variants and susceptibility to osteosarcoma. J Natl Cancer Inst. 2015;107(7).

23.

Joseph CG, Hwang H, Jiao Y, Wood LD, Kinde I, Wu J, et al. Exomic analysis of myxoid liposarcomas, synovial sarcomas, and osteosarcomas. Genes Chromosom Cancer. 2014;53(1):15–24.PubMed

24.

Bousquet M, Noirot C, Accadbled F, Sales de gauzy J, Castex MP, Brousset P, et al. Whole-exome sequencing in osteosarcoma reveals important heterogeneity of genetic alterations. Ann Oncol. 2016;27(4):738–44.PubMed

25.

Wang LL, Levy ML, Lewis RA, Chintagumpala MM, Lev D, Rogers M, et al. Clinical manifestations in a cohort of 41 Rothmund-Thomson syndrome patients. Am J Med Genet. 2001;102(1):11–7.PubMed

26.

Berman SD, Calo E, Landman AS, Danielian PS, Miller ES, West JC, et al. Metastatic osteosarcoma induced by inactivation of Rb and p53 in the osteoblast lineage. Proc Natl Acad Sci U S A. 2008;105(33):11851–6.

27.

Lin PP, Pandey MK, Jin F, Raymond AK, Akiyama H, Lozano G. Targeted mutation of p53 and Rb in mesenchymal cells of the limb bud produces sarcomas in mice. Carcinogenesis. 2009;30(10):1789–95.PubMedPubMedCentral

28.

Mutsaers AJ, Ng AJ, Baker EK, Russell MR, Chalk AM, Wall M, et al. Modeling distinct osteosarcoma subtypes in vivo using Cre: lox and lineage-restricted transgenic shRNA. Bone. 2013;55(1):166–78.PubMed

29.

Quist T, Jin H, Zhu JF, Smith-Fry K, Capecchi MR, Jones KB. The impact of osteoblastic differentiation on osteosarcomagenesis in the mouse. Oncogene. 2015;34(32):4278–84.PubMed

30.

Walkley CR, Qudsi R, Sankaran VG, Perry JA, Gostissa M, Roth SI, et al. Conditional mouse osteosarcoma, dependent on p53 loss and potentiated by loss of Rb, mimics the human disease. Genes Dev. 2008;22(12):1662–76.PubMedPubMedCentral

31.

Walia MK, Castillo-Tandazo W, Mutsaers AJ, Martin TJ, Walkley CR. Murine models of osteosarcoma: a piece of the translational puzzle. J Cell Biochem. 2018;119(6):4241–50.PubMed

32.

Steele CD, Tarabichi M, Oukrif D, Webster AP, Ye H, Fittall M, et al. Undifferentiated sarcomas develop through distinct evolutionary pathways. Cancer Cell. 2019;35(3):441–56 e8.PubMedPubMedCentral

33.

Mutsaers AJ, Walkley CR. Cells of origin in osteosarcoma: mesenchymal stem cells or osteoblast committed cells? Bone. 2014;62:56–63.PubMed

34.

Moriarity BS, Otto GM, Rahrmann EP, Rathe SK, Wolf NK, Weg MT, et al. A sleeping beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis. Nat Genet. 2015;47(6):615–24.PubMedPubMedCentral

35.

Pourebrahim R, Zhang Y, Liu B, Gao R, Xiong S, Lin PP, et al. Integrative genome analysis of somatic p53 mutant osteosarcomas identifies Ets2-dependent regulation of small nucleolar RNAs by mutant p53 protein. Genes Dev. 2017;31(18):1847–57.

36.

Scott MC, Temiz NA, Sarver AE, LaRue RS, Rathe SK, Varshney J, et al. Comparative transcriptome analysis quantifies immune cell transcript levels, metastatic progression, and survival in osteosarcoma. Cancer Res. 2018;78(2):326–37.PubMed

37.

Lu L, Harutyunyan K, Jin W, Wu J, Yang T, Chen Y, et al. RECQL4 regulates p53 function in vivo during Skeletogenesis. J Bone Miner Res. 2015;30(6):1077–89.PubMed

38.

Ng AJ, Walia MK, Smeets MF, Mutsaers AJ, Sims NA, Purton LE, et al. The DNA helicase Recql4 is required for normal osteoblast expansion and osteosarcoma formation. PLoS Genet. 2015;11(4):e1005160.PubMedPubMedCentral

39.

Tao J, Jiang MM, Jiang L, Salvo JS, Zeng HC, Dawson B, et al. Notch activation as a driver of osteogenic sarcoma. Cancer Cell. 2014;26(3):390–401.PubMedPubMedCentral

40.

Dougall WC. RANKL signaling in bone physiology and cancer. Curr Opin Support Palliat Care. 2007;1(4):317–22.PubMed

41.

Chen Y, Di Grappa MA, Molyneux SD, McKee TD, Waterhouse P, Penninger JM, et al. RANKL blockade prevents and treats aggressive osteosarcomas. Sci Transl Med. 2015;7(317):317ra197.PubMed

42.

Walkley CR, Shea JM, Sims NA, Purton LE, Orkin SH. Rb regulates interactions between hematopoietic stem cells and their bone marrow microenvironment. Cell. 2007;129(6):1081–95.PubMedPubMedCentral

43.

Roberts CW, Leroux MM, Fleming MD, Orkin SH. Highly penetrant, rapid tumorigenesis through conditional inversion of the tumor suppressor gene Snf5. Cancer Cell. 2002;2(5):415–25.PubMed

44.

Park D, Spencer JA, Koh BI, Kobayashi T, Fujisaki J, Clemens TL, et al. Endogenous bone marrow MSCs are dynamic, fate-restricted participants in bone maintenance and regeneration. Cell Stem Cell. 2012;10(3):259–72.PubMedPubMedCentral

45.

Kuhn R, Schwenk F, Aguet M, Rajewsky K. Inducible gene targeting in mice. Science. 1995;269(5229):1427–9.PubMed

46.

Shaw RJ, Bardeesy N, Manning BD, Lopez L, Kosmatka M, DePinho RA, et al. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell. 2004;6(1):91–9.PubMed

47.

• Han Y, Feng H, Sun J, Liang X, Wang Z, Xing W, et al. Lkb1 deletion in periosteal mesenchymal progenitors induces osteogenic tumors through mTORC1 activation. J Clin Invest. 2019;130. Evidence that loss of Lkb1 can lead to osteosarcoma-like tumors in vivo.

48.

Presneau N, Duhamel LA, Ye H, Tirabosco R, Flanagan AM, Eskandarpour M. Post-translational regulation contributes to the loss of LKB1 expression through SIRT1 deacetylase in osteosarcomas. Br J Cancer. 2017;117(3):398–408.PubMedPubMedCentral

49.

Watanabe A, Yoneyama S, Nakajima M, Sato N, Takao-Kawabata R, Isogai Y, et al. Osteosarcoma in Sprague-Dawley rats after long-term treatment with teriparatide (human parathyroid hormone (1-34)). J Toxicol Sci. 2012;37(3):617–29.PubMed

50.

Jolette J, Attalla B, Varela A, Long GG, Mellal N, Trimm S, et al. Comparing the incidence of bone tumors in rats chronically exposed to the selective PTH type 1 receptor agonist abaloparatide or PTH(1-34). Regul Toxicol Pharmacol. 2017;86:356–65.PubMed

51.

Vahle JL, Zuehlke U, Schmidt A, Westmore M, Chen P, Sato M. Lack of bone neoplasms and persistence of bone efficacy in cynomolgus macaques after long-term treatment with teriparatide [rhPTH(1-34)]. J Bone Miner Res. 2008;23(12):2033–9.PubMed

52.

Ho PW, Goradia A, Russell MR, Chalk AM, Milley KM, Baker EK, et al. Knockdown of PTHR1 in osteosarcoma cells decreases invasion and growth and increases tumor differentiation in vivo. Oncogene. 2015;34(22):2922–33.PubMed

53.

Walia MK, Ho PM, Taylor S, Ng AJ, Gupte A, Chalk AM, et al. Activation of PTHrP-cAMP-CREB1 signaling following p53 loss is essential for osteosarcoma initiation and maintenance. Elife. 2016;5.

54.

•• Walia MK, Taylor S, Ho PWM, Martin TJ, Walkley CR. Tolerance to sustained activation of the cAMP/Creb pathway activity in osteoblastic cells is enabled by loss of p53. Cell Death Dis. 2018;9(9):844. Provided evidence linking tolerance to elevated cAMP in osteoblasts with loss of p53. Demonstrated that inhibition of the transcriptional activity of CREB1 could be effective in OS.PubMedPubMedCentral

55.

• Stewart E, Federico S, Karlstrom A, Shelat A, Sablauer A, Pappo A, et al. The childhood solid tumor network: a new resource for the developmental biology and oncology research communities. Dev Biol. 2016;411(2):287–930. Description of a significant human OS tumor resource.PubMed

56.

Blattmann C, Thiemann M, Stenzinger A, Roth EK, Dittmar A, Witt H, et al. Establishment of a patient-derived orthotopic osteosarcoma mouse model. J Transl Med. 2015;13:136.

57.

Kito F, Oyama R, Sakumoto M, Takahashi M, Shiozawa K, Qiao Z, et al. Establishment and characterization of novel patient-derived osteosarcoma xenograft and cell line. In Vitro Cell Dev Biol Anim. 2018;54(7):528–36.

58.

Meohas W, Granato RA, Guimaraes JAM, Dias RB, Fortuna-Costa A, Duarte MEL. Patient-derived xenografts as a preclinical model for bone sarcomas. Acta Ortop Bras. 2018;26(2):98–102.PubMedPubMedCentral

59.

•• Sayles LC, Breese MR, Koehne AL, Leung SG, Lee AG, Liu HY, et al. Genome-informed targeted therapy for osteosarcoma. Cancer Discov. 2019;9(1):46–63. Describes a genome informed approach to selection of targeted agents for OS therapy.PubMed

60.

Schiffman JD, Breen M. Comparative oncology: what dogs and other species can teach us about humans with cancer. Philos Trans R Soc Lond B Biol Sci. 2015;370(1673).

61.

Withrow SJ, Wilkins RM. Cross talk from pets to people: translational osteosarcoma treatments. ILAR J. 2010;51(3):208–13.PubMed

62.

Fan TM, Selting KA. Exploring the potential utility of pet dogs with cancer for studying radiation-induced immunogenic cell death strategies. Front Oncol. 2018;8:680.PubMed

63.

Tarone L, Barutello G, Iussich S, Giacobino D, Quaglino E, Buracco P, et al. Naturally occurring cancers in pet dogs as pre-clinical models for cancer immunotherapy. Cancer Immunol Immunother. 2019.

64.

Fenger JM, London CA, Kisseberth WC. Canine osteosarcoma: a naturally occurring disease to inform pediatric oncology. ILAR J. 2014;55(1):69–85.PubMed

65.

•• Shao YW, Wood GA, Lu J, Tang QL, Liu J, Molyneux S, et al. Cross-species genomics identifies DLG2 as a tumor suppressor in osteosarcoma. Oncogene. 2019;38(2):291–8. Evidence of the utility of canine OS for target and genetic discovery.PubMed

66.

•• Sakthikumar S, Elvers I, Kim J, Arendt ML, Thomas R, Turner-Maier J, et al. SETD2 is recurrently mutated in whole-exome sequenced canine osteosarcoma. Cancer Res. 2018;78(13):3421–31. Evidence of the utility of canine OS for target and genetic discovery.PubMed

67.

Al-Khan AA, Gunn HJ, Day MJ, Tayebi M, Ryan SD, Kuntz CA, et al. Immunohistochemical validation of spontaneously arising canine osteosarcoma as a model for human osteosarcoma. J Comp Pathol. 2017;157(4):256–65.PubMed

68.

Roy J, Wycislo KL, Pondenis H, Fan TM, Das A. Comparative proteomic investigation of metastatic and non-metastatic osteosarcoma cells of human and canine origin. PLoS One. 2017;12(9):e0183930.PubMedPubMedCentral

69.

Heyman SJ, Diefenderfer DL, Goldschmidt MH, Newton CD. Canine axial skeletal osteosarcoma. A retrospective study of 116 cases (1986 to 1989). Vet Surg. 1992;21(4):304–10.PubMed

70.

Mirabello L, Troisi RJ, Savage SA. Osteosarcoma incidence and survival rates from 1973 to 2004: data from the surveillance, epidemiology, and end results program. Cancer. 2009;115(7):1531–43.PubMed

71.

Wycislo KL, Fan TM. The immunotherapy of canine osteosarcoma: a historical and systematic review. J Vet Intern Med. 2015;29(3):759–69.PubMedPubMedCentral

72.

MacEwen EG, Kurzman ID, Rosenthal RC, Smith BW, Manley PA, Roush JK, et al. Therapy for osteosarcoma in dogs with intravenous injection of liposome-encapsulated muramyl tripeptide. J Natl Cancer Inst. 1989;81(12):935–8.PubMed

73.

Meyers PA, Schwartz CL, Krailo MD, Healey JH, Bernstein ML, Betcher D, et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival--a report from the Children’s Oncology Group. J Clin Oncol. 2008;26(4):633–8.

74.

Brady SW, Ma X, Bahrami A, Satas G, Wu G, Newman S, et al. The clonal evolution of metastatic osteosarcoma as shaped by cisplatin treatment. Mol Cancer Res. 2019;17(4):895–906.PubMed

75.

Monks NR, Cherba DM, Kamerling SG, Simpson H, Rusk AW, Carter D, et al. A multi-site feasibility study for personalized medicine in canines with osteosarcoma. J Transl Med. 2013;11:158.

76.

Fowles JS, Brown KC, Hess AM, Duval DL, Gustafson DL. Intra- and interspecies gene expression models for predicting drug response in canine osteosarcoma. BMC Bioinformatics. 2016;17:93.PubMedPubMedCentral

77.

• Kumar RM, Arlt MJ, Kuzmanov A, Born W, Fuchs B. Sunitinib malate (SU-11248) reduces tumour burden and lung metastasis in an intratibial human xenograft osteosarcoma mouse model. Am J Cancer Res. 2015;5(7):2156–68.PubMedPubMedCentral

78.

• Kim C, Matsuyama A, Mutsaers AJ, Woods JP. Retrospective evaluation of toceranib (palladia) treatment for canine metastatic appendicular osteosarcoma. Can Vet J. 2017;58(10):1059–64.PubMedPubMedCentral

79.

• Laver T, London CA, Vail DM, Biller BJ, Coy J, Thamm DH. Prospective evaluation of toceranib phosphate in metastatic canine osteosarcoma. Vet Comp Oncol. 2018;16(1):E23–E9.PubMed

80.

• London CA, Gardner HL, Mathie T, Stingle N, Portela R, Pennell ML, et al. Impact of toceranib/piroxicam/cyclophosphamide maintenance therapy on outcome of dogs with appendicular osteosarcoma following amputation and carboplatin chemotherapy: a multi-institutional study. PLoS One. 2015;10(4):e0124889. Collectively, reference entries [77–80] demonstrate the strength of combining mutliple species to test new agents prior to prioritisation for human clinial trial.PubMedPubMedCentral

Titel: Osteosarcoma in the Post Genome Era: Preclinical Models and Approaches to Identify Tractable Therapeutic Targets
verfasst von: Wilson Castillo-Tandazo
Anthony J. Mutsaers
Carl R. Walkley
Publikationsdatum: 16.09.2019
Verlag: Springer US
Erschienen in: Current Osteoporosis Reports / Ausgabe 5/2019
Print ISSN: 1544-1873
Elektronische ISSN: 1544-2241
DOI: https://doi.org/10.1007/s11914-019-00534-w

Arthropedia

Grundlagenwissen der Arthroskopie und Gelenkchirurgie. Erweitert durch Fallbeispiele, Videos und Abbildungen.
» Jetzt entdecken

Neu im Fachgebiet Orthopädie und Unfallchirurgie

25.04.2024 | Hypertonie | Nachrichten

Update Orthopädie und Unfallchirurgie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Osteosarcoma in the Post Genome Era: Preclinical Models and Approaches to Identify Tractable Therapeutic Targets

Abstract

Purpose of Review

Recent Findings

Summary

Arthropedia

Neu im Fachgebiet Orthopädie und Unfallchirurgie

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

Ärztliche Empathie hilft gegen Rückenschmerzen

Stereotaktische Radiatio schlägt konventionelle Bestrahlung

Vorsicht mit hohen NSAR-Dosen bei ankylosierender Spondylitis!

Update Orthopädie und Unfallchirurgie

Springer Medizin

Abstract

Purpose of Review

Recent Findings

Summary

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 5/2019

The Effect of Type 2 Diabetes on Bone Biomechanics

Physicochemical Niche Conditions and Mechanosensing by Osteocytes and Myocytes

Breast Cancer Dormancy in Bone

Osteoglycin and Bone—a Systematic Review

Controversies in the Management of Secondary Hyperparathyroidism in Chronic Kidney Disease

The Role of Lower-Limb Geometry in the Pathophysiology of Atypical Femoral Fracture

Arthropedia

Neu im Fachgebiet Orthopädie und Unfallchirurgie

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

Ärztliche Empathie hilft gegen Rückenschmerzen

Stereotaktische Radiatio schlägt konventionelle Bestrahlung

Vorsicht mit hohen NSAR-Dosen bei ankylosierender Spondylitis!

Update Orthopädie und Unfallchirurgie