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Osteoprotegerin Treatment Impairs Remodeling and Apparent Material Properties of Callus Tissue without Influencing Structural Fracture Strength

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Abstract

The influence of osteoprotegerin (OPG) treatment on callus formation, callus tissue structural strength, apparent material properties, and histology of tibia fractures in rats was investigated after 3 weeks and 8 weeks of healing. OPG was given intravenously (10 mg/kg twice weekly) during the entire observation period, and control animals with fractures received vehicle only. When compared with control fractures after 3 weeks of healing, OPG treatment reduced the number of osteoclasts in the callus tissue (93%, P < 0.001) and hampered resorption of genuine cortical bone in the fracture line; OPG treatment did not influence callus dimensions, callus bone mineral content (BMC), fracture structural strength, or callus tissue apparent material properties. When compared with control fractures after 8 weeks of healing; OPG treatment reduced the number of osteoclasts in callus tissue (92%, P < 0.001), augmented callus dimensions (anteriorposterior diameter: 12%, P = 0.034, mediolateral diameter: 13%, P = 0.013), and increased callus BMC (50%, P = 0.007); OPG treatment hampered deposition of new woven bone at the fracture line of the genuine cortical bone (new woven bone present in all vehicle animals, but only in 13% of the OPG-treated animals (P < 0.001)); OPG treatment did not influence structural strength of the fractures, but decreased apparent material properties of the callus tissue (ultimate stress: 51%, P < 0.001; elastic modulus: 42%, P = 0.033). The experiment demonstrates that OPG treatment does not influence the early callus expansion and fracture strength. However, during the subsequent period of remodelling, OPG treatment impairs the normal remodeling and consolidation processes.

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References

  1. LC Hofbauer AE Heufelder (2001) ArticleTitleRole of receptor activator of nuclear .factor-kappaB ligand and osteoprotegerin in bone cell biology J Mol Med 79 243–253 Occurrence Handle1:CAS:528:DC%2BD3MXlslWgt78%3D Occurrence Handle10.1007/s001090100226

    Article  CAS  Google Scholar 

  2. EM Schwarz RJ O’Keefe (2000) ArticleTitleBreakthrough in bone: the molecular mechanism of osteoclast/osteoblast coupling revealed Curr Opin Orthop 11 329–335 Occurrence Handle10.1097/00001433-200010000-00001

    Article  Google Scholar 

  3. SL Teitelbaum (2000) ArticleTitleBone resorption by osteoclasts Science 289 1504–1508 Occurrence Handle1:CAS:528:DC%2BD3cXmt1KgsLk%3D Occurrence Handle10.1126/science.289.5484.1504

    Article  CAS  Google Scholar 

  4. WS Simonet DL Lacey CR Dunstan M Kelley MS Chang R Luthy HQ Nguyen S Wooden L Bennett T Boone G Shimamoto M DeRose R Elliott A Colombero HL Tan G Trail J Sullivan E Davy N Bucay L Renshaw-Gegg TM Hughes D Hill W Pattison P Campbell WJ Boyle (1997) ArticleTitleOsteoprotegerin: a novel secreted protein involved in the regulation of bone density Cell 89 309–319 Occurrence Handle1:CAS:528:DyaK2sXislCgtLc%3D Occurrence Handle10.1016/S0092-8674(00)80209-3

    Article  CAS  Google Scholar 

  5. M Shimizu-Ishiura F Kawana T Sasaki (2002) ArticleTitleOsteoprotegerin administration reduces femoral bone loss in ovariectomized mice via impairment of osteoclast structure and function J Electron Microsc 51 315–325 Occurrence Handle1:CAS:528:DC%2BD38XovFOqu70%3D Occurrence Handle10.1093/jmicro/51.5.315

    Article  CAS  Google Scholar 

  6. YY Kong U Feige I Sarosi B Bolon A Tafuri S Morony C Capparelli J Li R Elliott S McCabe T Wong G Campagnuolo E Moran ER Bogoch G Van LT Nguyen PS Ohashi DL Lacey E Fish WJ Boyle JM Penninger (1999) ArticleTitleActivated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand Nature 402 304–309 Occurrence Handle1:CAS:528:DyaK1MXnvFShsLg%3D Occurrence Handle10.1038/46303

    Article  CAS  Google Scholar 

  7. S Morony C Capparelli I Sarosi DL Lacey CR Dunstan PJ Kostenuik (2001) ArticleTitleOsteoprotegerin inhibits osteolysis and decreases skeletal tumor burden in syngeneic and nude mouse models of experimental bone metastasis Cancer Res 61 4432–4436 Occurrence Handle1:CAS:528:DC%2BD3MXktlWjsrs%3D Occurrence Handle11389072

    CAS  PubMed  Google Scholar 

  8. C Capparelli PJ Kostenuik S Morony C Starnes B Weimann G Van S Scully M Qi DL Lacey CR Dunstan (2000) ArticleTitleOsteoprotegerin prevents and reverses hypercalcemia in a murine model of humoral hypercalcemia of malignancy Cancer Res 60 783–787 Occurrence Handle1:CAS:528:DC%2BD3cXhs1Siur4%3D Occurrence Handle10706080

    CAS  PubMed  Google Scholar 

  9. J Zhang J Dai Y Qi DL Lin P Smith C Strayhorn A Mizokami Z Fu J Westman ET Keller (2001) ArticleTitleOsteoprotegerin inhibits prostate cancer-induced osteoclastogenesis and prevents prostate tumor growth in the bone J Clin Invest 107 1235–1244 Occurrence Handle1:CAS:528:DC%2BD3MXjsl2ntr0%3D Occurrence Handle10.1172/JCI11685

    Article  CAS  Google Scholar 

  10. M Ulrich-Vinther EE Carmody JJ Goater K Søballe RJ O’Keefe EM Schwarz (2002) ArticleTitleRecombinant adeno-associated virus-mediated osteoprotegerin gene therapy inhibits wear debris-induced osteolysis J Bone Joint Surg Am 84 1405–1412 Occurrence Handle10.2106/00004623-200208000-00017

    Article  Google Scholar 

  11. JJ Goater RJ O’Keefe RN Rosier JE Puzas EM Schwarz (2002) ArticleTitleEfficacy of ex vivo OPG gene therapy in preventing wear debris induced osteolysis J Orthop Res 20 169–173 Occurrence Handle1:CAS:528:DC%2BD38XjtVGgurc%3D Occurrence Handle10.1016/S0736-0266(01)00083-3

    Article  CAS  Google Scholar 

  12. PJ Bekker D Holloway A Nakanishi M Arrighi PT Leese CR Dunstan (2001) ArticleTitleThe effect of a single dose of osteoprotegerin in postmenopausal women J Bone Miner Res 16 348–360 Occurrence Handle1:CAS:528:DC%2BD3MXptlOquw%3D%3D Occurrence Handle10.1359/jbmr.2001.16.2.348

    Article  CAS  Google Scholar 

  13. T Kon TJ Cho T Aizawa M Yamazaki N Nooh D Graves LC Gerstenfeld TA Einhorn (2001) ArticleTitleExpression of osteoprotegerin, receptor activator of NF-kappaB ligand (osteoprotegerin ligand) and related proinflammatory cytokines during fracture healing J Bone Miner Res 16 1004–1014 Occurrence Handle1:CAS:528:DC%2BD3MXkt1Oqsr8%3D Occurrence Handle10.1359/jbmr.2001.16.6.1004

    Article  CAS  Google Scholar 

  14. TT Andreassen C Fledelius C Ejersted H Oxlund (2001) ArticleTitleIncreases in callus formation and mechanical strength of healing fractures in old rats treated with parathyroid hormone Acta Orthop Scand 12 304–307 Occurrence Handle10.1080/00016470152846673

    Article  Google Scholar 

  15. TT Andreassen C Ejersted H Oxlund (1999) ArticleTitleIntermittent parathyroid hormone (1–34) treatment increases callus formation and mechanical strength of healing rat fractures J Bone Miner Res 14 960–968 Occurrence Handle1:CAS:528:DyaK1MXjvFKqurw%3D Occurrence Handle10.1359/jbmr.1999.14.6.960

    Article  CAS  Google Scholar 

  16. TT Andreassen PH. Jorgensen A Flyvbjerg H Orskov H Oxlund (1995) ArticleTitleGrowth hormone stimulates bone formation and strength of cortical bone in aged rats J Bone Miner Res 10 1057–1067 Occurrence Handle1:CAS:528:DyaK2MXntVakt7w%3D Occurrence Handle10.1002/jbmr.5650100710

    Article  CAS  Google Scholar 

  17. RG Erben (1997) ArticleTitleEmbedding of bone samples in methylmethacrylate: an improved method suitable for bone histomorphometry, histochemistry, and immunohistochemistry J Histochem Cytochem 45 307–313 Occurrence Handle1:CAS:528:DyaK2sXhvVylsLk%3D Occurrence Handle10.1177/002215549704500215

    Article  CAS  Google Scholar 

  18. WC Hayes (1991) Biomechanics of cortical and trabecullar bone: Implications for assessment of fracture risk VC Mow WC Hayes (Eds) Basic Orthopaedic Biomechanics Raven Press New York 93–142

    Google Scholar 

  19. TT Andreassen GE Willick P Morley JF Whitfield (2004) ArticleTitleTreatment with parathyroid hormone hPTH(1–34), hPTH(1–31), and monocyclic hPTH(1–31) enhances fracture strength and callus amount after withdrawal fracture strength and callus mechanical quality continue to increase Calc Tissue Int 74 351–356 Occurrence Handle1:CAS:528:DC%2BD2cXjslWrtLk%3D Occurrence Handle10.1007/s00223-003-0093-6

    Article  CAS  Google Scholar 

  20. LM Flick JM Weaver M Ulrich-Vinther F Abuzzahab X Zhang WC Dougall D Anderson RJ O’Keefe EM Schwarz (2003) ArticleTitleEffects of receptor activator of NFkappaB (RANK) signaling blockade on fracture healing J Orthop Res 21 676–684 Occurrence Handle1:CAS:528:DC%2BD3sXkt1Oksbk%3D Occurrence Handle10.1016/S0736-0266(03)00011-1

    Article  CAS  Google Scholar 

  21. TM Lenehan M Balligand DM Nunamaker FE Wood SuffixJr (1985) ArticleTitleEffect of EHDP on fracture healing in dogs J Orthop Res 3 499–507 Occurrence Handle1:CAS:528:DyaL28Xmt1SgtQ%3D%3D Occurrence Handle10.1002/jor.1100030413

    Article  CAS  Google Scholar 

  22. MT Nyman P Paavolainen TS Lindholm (1993) ArticleTitleClodronate increases the calcium content in fracture callus. An experimental study in rats Arch Orthop Trauma Surg 112 228–231 Occurrence Handle1:STN:280:DyaK2c%2FjtFequg%3D%3D Occurrence Handle10.1007/BF00451880

    Article  CAS  Google Scholar 

  23. MT Nyman T Gao TC Lindholm TS Lindholm (1996) ArticleTitleHealing of a tibial double osteotomy is modified by clodronate administration Arch Orthop Trauma Surg 115 111–114 Occurrence Handle1:STN:280:DyaK2s%2Fns1KjtA%3D%3D Occurrence Handle10.1007/BF00573453

    Article  CAS  Google Scholar 

  24. CP Peter WO Cook DM Nunamaker MT Provost JG Seedor GA Rodan (1996) ArticleTitleEffect of alendronate on fracture healing and bone remodeling in dogs J Orthop Res 14 74–79 Occurrence Handle1:CAS:528:DyaK28Xitl2jtrs%3D Occurrence Handle10.1002/jor.1100140113

    Article  CAS  Google Scholar 

  25. JE Madsen T Berg-Larsen OJ Kirkeby JA Falch L Nordsletten (1998) ArticleTitleNo adverse effects of clodronate on fracture healing in rats Acta Orthop Scand 69 532–536 Occurrence Handle1:STN:280:DyaK1M%2FntVyrsw%3D%3D Occurrence Handle10.3109/17453679808997793

    Article  CAS  Google Scholar 

  26. J Li S Mori Y Kaji T Mashiba J Kawanishi H Norimatsu (1999) ArticleTitleEffect of bisphosphonate (incadronate) on fracture healing of long bones in rats J Bone Miner Res 14 969–979 Occurrence Handle1:CAS:528:DyaK1MXjvFKqur0%3D Occurrence Handle10.1359/jbmr.1999.14.6.969

    Article  CAS  Google Scholar 

  27. J Li S Mori Y Kaji J Kawanishi T Akiyama H Norimatsu (2000) ArticleTitleConcentration of bisphosphonate (incadronate) in callus area and its effects on fracture healing in rats J Bone Miner Res 15 2042–2051 Occurrence Handle1:STN:280:DC%2BD3cvnslSruw%3D%3D Occurrence Handle10.1359/jbmr.2000.15.10.2042

    Article  CAS  Google Scholar 

  28. C Li S Mori J Li Y Kaji T Akiyama J Kawanishi H Norimatsu (2001) ArticleTitleLong-term effect of incadronate disodium (YM-175) on fracture healing of femoral shaft in growing rats J Bone Miner Res 16 429–436 Occurrence Handle1:CAS:528:DC%2BD3MXhvFKksbg%3D Occurrence Handle10.1359/jbmr.2001.16.3.429

    Article  CAS  Google Scholar 

  29. Y Cao S Mori T Mashiba MS Westmore L Ma M Sato T Akiyama L Shi S Komatsubara K Miyamoto H Norimatsu (2002) ArticleTitleRaloxifene, estrogen, and alendronate affect the processes of fracture repair differently in ovariectomized rats J Bone Miner Res 17 2237–2246 Occurrence Handle1:CAS:528:DC%2BD38XpsV2lsb4%3D Occurrence Handle10.1359/jbmr.2002.17.12.2237

    Article  CAS  Google Scholar 

  30. A Koivukangas J Tuukkanen K Kippo T Jamsa R Hannuniemi I Pasanen K Vaananen P Jalovaara (2003) ArticleTitleLong-term administration of clodronate does not prevent fracture healing in rats Clin Orthop 408 268–278 Occurrence Handle10.1097/00003086-200303000-00036

    Article  Google Scholar 

  31. R Tarvainen H Olkkonen T Nevalainen P Hyvonen I Arnala E Alhava (1994) ArticleTitleEffect of clodronate on fracture healing in denervated rats Bone 15 701–705 Occurrence Handle1:CAS:528:DyaK2cXmvFaksbY%3D Occurrence Handle10.1016/8756-3282(94)90320-4

    Article  CAS  Google Scholar 

  32. PJ Kostenuik C Capparelli S Morony S Adamu G Shimamoto V Shen DL Lacey CR Dunstan (2001) ArticleTitleOPG and PTH-(1-34) have additive effects on bone density and mechanical strength in osteopenic ovariectomized rats Endocrinology 142 4295–4304 Occurrence Handle1:CAS:528:DC%2BD3MXnt1ert70%3D Occurrence Handle10.1210/endo.142.10.8437

    Article  CAS  Google Scholar 

  33. S Capparelli C-Morony K Warmington S Adamu D Lacey CR Dunstan B Stouch S Martin PJ Kostenuik (2003) ArticleTitleSustained antiresorptive effects after a single treatment with human recombinant osteoprotegerin (OPG): a pharmacodynamic and pharmacokinetic analysis in rats J Bone Miner Res 18 852–858 Occurrence Handle10.1359/jbmr.2003.18.5.852

    Article  Google Scholar 

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Acknowledgments

This study was supported by The Beckett-Foundation, Denmark, and The Augustinus Foundation, Denmark hOPG was kindly provided by Amgen, Thousand Oaks, CA. We thank Jytte Utoft and Merete Fischer for their skilled technical assistance, and Thomas Ledet, Department of Biochemical Pathology, University of Aarhus, Denmark, for providing laboratory facilities required for the hOPG ELISA analyses.

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  1. Department of Orthopaedics, Aarhus University Hospital, Aarhus, Denmark

    M. Ulrich-Vinther

  2. Department of Connective Tissue Biology, Institute of Anatomy, University of Aarhus, Aarhus, Denmark

    T.T. Andreassen

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Correspondence to M. Ulrich-Vinther.

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Ulrich-Vinther, M., Andreassen, T. Osteoprotegerin Treatment Impairs Remodeling and Apparent Material Properties of Callus Tissue without Influencing Structural Fracture Strength. Calcif Tissue Int 76, 280–286 (2005). https://doi.org/10.1007/s00223-004-0126-9

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