Skip to main content

Advertisement

SpringerLink
Log in

The use of 18F-fluoride and 18F-FDG PET scans to assess fracture healing in a rat femur model

  • Original article
  • Published:
European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Currently available diagnostic techniques can be unreliable in the diagnosis of delayed fracture healing in certain clinical situations, which can lead to increased complication rates and costs to the health care system. This study sought to determine the utility of positron emission tomography (PET) scanning with 18F-fluoride ion, which localizes in regions of high osteoblastic activity, and 18F-fluorodeoxyglucose (FDG), an indicator of cellular glucose metabolism, in assessing bone healing in a rat femur fracture model.

Methods

Fractures were created in the femurs of immunocompetent rats. Animals in group I had a fracture produced via a manual three-point bending technique. Group II animals underwent a femoral osteotomy with placement of a 2-mm silastic spacer at the fracture site. Fracture healing was assessed with plain radiographs, 18F-fluoride, and 18F-FDG PET scans at 1, 2, 3, and 4-week time points after surgery. Femoral specimens were harvested for histologic analysis and manual testing of torsional and bending strength 4 weeks after surgery.

Results

All fractures in group I revealed abundant callus formation and bone healing, while none of the nonunion femurs were healed via assessment with manual palpation, radiographic, and histologic evaluation at the 4-week time point. 18F-fluoride PET images of group I femurs at successive 1-week intervals revealed progressively increased signal uptake at the union site during fracture repair. In contrast, minimal tracer uptake was seen at the fracture sites in group II at all time points after surgery. Data analysis revealed statistically significant differences in mean signal intensity between groups I and II at each weekly interval. No significant differences between the two groups were seen using 18F-FDG PET imaging at any time point.

Conclusion

This study suggests that 18F-fluoride PET imaging, which is an indicator of osteoblastic activity in vivo, can identify fracture nonunions at an early time point and may have a role in the assessment of longitudinal fracture healing. PET scans using 18F-FDG were not helpful in differentiating metabolic activity between successful and delayed bone healing.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Heppenstall RB. The present role of bone graft surgery in treating nonunion. Orthop Clin North Am 1984;15:113–23.

    CAS  PubMed  Google Scholar 

  2. Jupiter JB, First K, Gallico GG 3rd, May JW. The role of external fixation in the treatment of posttraumatic osteomyelitis. J Orthop Trauma 1988;2:79–93.

    Article  CAS  PubMed  Google Scholar 

  3. Hulth A. Current concepts of fracture healing. Clin Orthop Relat Res 1989;49:265–84.

    Google Scholar 

  4. Rodriguez-Merchan EC, Forriol F. Nonunion: general principles and experimental data. Clin Orthop Relat Res 2004;419:4–12.

    Article  PubMed  Google Scholar 

  5. Zlowodzki M, Obremskey WT, Thomison JB, Kregor PJ. Functional outcome after treatment of lower-extremity nonunions. J Trauma 2005;58:312–7.

    PubMed  Google Scholar 

  6. Bowen CV, Botsford DJ, Hudak PL, Evans PJ. Microsurgical treatment of septic nonunion of the tibia. Quality of life results. Clin Orthop Relat Res 1996;332:52–61.

    Article  PubMed  Google Scholar 

  7. Sprague S, Bhandari M. An economic evaluation of early versus delayed operative treatment in patients with closed tibial shaft fractures. Arch Orthop Trauma Surg 2002;122:315–23.

    PubMed  Google Scholar 

  8. Bhandari M, Adili A, Leone J, Lachowski RJ, Kwok DC. Early versus delayed operative management of closed tibial fractures. Clin Orthop Relat Res 1999;368:230–9.

    Article  PubMed  Google Scholar 

  9. Heckman JD, Sarasohn-Kahn J. The economics of treating tibia fractures. The cost of delayed unions. Bull Hosp Jt Dis 1997;56:63–72.

    CAS  PubMed  Google Scholar 

  10. Ikeda K, Tomita K, Hashimoto F, Morikawa S. Long-term follow-up of vascularized bone grafts for the reconstruction of tibial nonunion: evaluation with computed tomographic scanning. J Trauma 1992;32:693–7.

    Article  CAS  PubMed  Google Scholar 

  11. Savolaine ER, Ebraheim N. Assessment of femoral neck nonunion with multiplanar computed tomography reconstruction. Orthopedics 2000;23:713–5.

    CAS  PubMed  Google Scholar 

  12. Shefelbine SJ, Simon U, Claes L, Gold A, Gabet Y, Bab I, et al. Prediction of fracture callus mechanical properties using micro-CT images and voxel-based finite element analysis. Bone 2005;36:480–8.

    Article  PubMed  Google Scholar 

  13. Belsole RJ, Hilbelink DR, Llewellyn JA, Dale M, Greene TL, Rayhack JM. Computed analyses of the pathomechanics of scaphoid waist nonunions. J Hand Surg [Am] 1991;16:899–906.

    CAS  Google Scholar 

  14. Kuhlman JE, Fishman EK, Ney DR, Brooker AF Jr, Magid D. Nonunion of acetabular fractures: evaluation with interactive multiplanar CT. J Orthop Trauma 1989;3:33–40.

    Article  CAS  PubMed  Google Scholar 

  15. Kuhlman JE, Fishman EK, Magid D, Scott WW Jr, Brooker AF, Siegelman SS. Fracture nonunion: CT assessment with multiplanar reconstruction. Radiology 1988;167:483–8.

    CAS  PubMed  Google Scholar 

  16. Bhattacharyya T, Bouchard KA, Phadke A, Meigs JB, Kassarjian A, Salamipour H. The accuracy of computed tomography for the diagnosis of tibial nonunion. J Bone Joint Surg Am 2006;88:692–7.

    Article  PubMed  Google Scholar 

  17. Moed BR, Kim EC, van Holsbeeck M, Schaffler MB, Subramanian S, Bouffard JA, et al. Ultrasound for the early diagnosis of tibial fracture healing after static interlocked nailing without reaming: histologic correlation using a canine model. J Orthop Trauma 1998;12:200–5.

    Article  CAS  PubMed  Google Scholar 

  18. Moed BR, Subramanian S, van Holsbeeck M, Watson JT, Cramer KE, Karges DE, et al. Ultrasound for the early diagnosis of tibial fracture healing after static interlocked nailing without reaming: clinical results. J Orthop Trauma 1998;12:206–13.

    Article  CAS  PubMed  Google Scholar 

  19. Moed BR, Watson JT, Goldschmidt P, van Holsbeeck M. Ultrasound for the early diagnosis of fracture healing after interlocking nailing of the tibia without reaming. Clin Orthop Relat Res 1995;310:137–44.

    PubMed  Google Scholar 

  20. Derbyshire ND, Simpson AH. A role for ultrasound in limb lengthening. Br J Radiol 1992;65:576–80.

    CAS  PubMed  Google Scholar 

  21. Young JW, Kostrubiak IS, Resnik CS, Paley D. Sonographic evaluation of bone production at the distraction site in Ilizarov limb-lengthening procedures. AJR Am J Roentgenol 1990;154:125–8.

    CAS  PubMed  Google Scholar 

  22. Hirata T, Konishiike T, Kawai A, Sato T, Inoue H. Dynamic magnetic resonance imaging of femoral head perfusion in femoral neck fracture. Clin Orthop Relat Res 2001;393:294–301.

    Article  PubMed  Google Scholar 

  23. Dailiana ZH, Zachos V, Varitimidis S, Papanagiotou P, Karantanas A, Malizos KN. Scaphoid nonunions treated with vascularised bone grafts: MRI assessment. Eur J Radiol 2004;50:217–24.

    Article  CAS  PubMed  Google Scholar 

  24. De Schrijver F, De Smet L. Isolated fracture of the capitate: the value of MRI in diagnosis and follow up. Acta Orthop Belg 2002;68:310–5.

    PubMed  Google Scholar 

  25. Lee C, Dorcil J, Radomisli TE. Nonunion of the spine: a review. Clin Orthop Relat Res 2004;419:71–5.

    Article  PubMed  Google Scholar 

  26. Kuschner SH, Lane CS, Brien WW, Gellman H. Scaphoid fractures and scaphoid nonunion. Diagnosis and treatment. Orthop Rev 1994;23:861–71.

    CAS  PubMed  Google Scholar 

  27. Rayan GM. Occult wrist pain due to capitate nonunion. South Med J 1994;87:402–4.

    CAS  PubMed  Google Scholar 

  28. Schelstraete K, Daneels F, Obrie E. Technetium-99m-diphosphonate, gallium-67 and labeled leukocyte scanning techniques in tibial nonunion. Acta Orthop Belg 1992;58 Suppl 1:168–72.

    PubMed  Google Scholar 

  29. O'Reilly RJ, Cook DJ, Gaffney RD, Angel KR, Paterson DC. Can serial scintigraphic studies detect delayed fracture union in man? Clin Orthop Relat Res 1981;160:227–32.

    PubMed  Google Scholar 

  30. Ebraheim NA, Savolaine ER, Patel A, Skie M, Jackson WT. Assessment of tibial fracture union by 35–45 degrees internal oblique radiographs. J Orthop Trauma 1991;5:349–50.

    Article  CAS  PubMed  Google Scholar 

  31. Sorensen J, Ullmark G, Langstrom B, Nilsson O. Rapid bone and blood flow formation in impacted morselized allografts: positron emission tomography (PET) studies on allografts in 5 femoral component revisions of total hip arthroplasty. Acta Orthop Scand 2003;74:633–43.

    Article  PubMed  Google Scholar 

  32. Blau M, Nagler W, Bender MA. Fluorine-18: a new isotope for bone scanning. J Nucl Med 1962;3:332–4.

    CAS  PubMed  Google Scholar 

  33. Narita N, Kato K, Nakagaki H, Ohno N, Kameyama Y, Weatherell JA. Distribution of fluoride concentration in the rat’s bone. Calcif Tissue Int 1990;46:200–4.

    Article  CAS  PubMed  Google Scholar 

  34. Toegel S, Hoffmann O, Wadsak W, Ettlinger D, Mien LK, Wiesner K, et al. Uptake of bone-seekers is solely associated with mineralisation! A study with 99mTc-MDP, 153Sm-EDTMP and 18F-fluoride on osteoblasts. Eur J Nucl Med Mol Imaging 2006;33:491–4.

    Article  PubMed  Google Scholar 

  35. Blau M, Ganatra R, Bender MA. 18F-fluoride for bone imaging. Semin Nucl Med 1972;2:31–7.

    Article  CAS  PubMed  Google Scholar 

  36. Reeve J, Arlot M, Wootton R, Edouard C, Tellez M, Hesp R, et al. Skeletal blood flow, iliac histomorphometry, and strontium kinetics in osteoporosis: a relationship between blood flow and corrected apposition rate. J Clin Endocrinol Metab 1988;66:1124–31.

    Article  CAS  PubMed  Google Scholar 

  37. Hawkins RA, Choi Y, Huang SC, Hoh CK, Dahlbom M, Schiepers C, et al. Evaluation of the skeletal kinetics of fluorine-18-fluoride ion with PET. J Nucl Med 1992;33:633–42.

    CAS  PubMed  Google Scholar 

  38. Schiepers C, Nuyts J, Bormans G, Dequeker J, Bouillon R, Mortelmans L, et al. Fluoride kinetics of the axial skeleton measured in vivo with fluorine-18-fluoride PET. J Nucl Med 1997;38:1970–6.

    CAS  PubMed  Google Scholar 

  39. Cook GJ, Fogelman I. The role of positron emission tomography in the management of bone metastases. Cancer 2000;88(12 Suppl):2927–33.

    Article  CAS  PubMed  Google Scholar 

  40. Blake GM, Park-Holohan SJ, Cook GJ, Fogelman I. Quantitative studies of bone with the use of 18F-fluoride and 99mTc-methylene diphosphonate. Semin Nucl Med 2001;31:28–49.

    Article  CAS  PubMed  Google Scholar 

  41. Schwartz Z, Shani J, Soskolne WA, Touma H, Amir D, Sela J. Uptake and biodistribution of technetium-99m-MD32P during rat tibial bone repair. J Nucl Med 1993;34:104–8.

    CAS  PubMed  Google Scholar 

  42. Berger F, Lee YP, Loening AM, Chatziioannou A, Freedland SJ, Leahy R, et al. Whole-body skeletal imaging in mice utilizing microPET: optimization of reproducibility and applications in animal models of bone disease. Eur J Nucl Med Mol Imaging 2002;29:1225–36.

    Article  CAS  PubMed  Google Scholar 

  43. Even-Sapir E, Metser U, Flusser G, Zuriel L, Kollender Y, Lerman H, et al. Assessment of malignant skeletal disease: initial experience with 18F-fluoride PET/CT and comparison between 18F-fluoride PET and 18F-fluoride PET/CT. J Nucl Med 2004;45:272–8.

    PubMed  Google Scholar 

  44. Frost ML, Fogelman I, Blake GM, Marsden PK, Cook G Jr. Dissociation between global markers of bone formation and direct measurement of spinal bone formation in osteoporosis. J Bone Miner Res 2004;19:1797–804.

    Article  CAS  PubMed  Google Scholar 

  45. Cook GJ, Blake GM, Marsden PK, Cronin B, Fogelman I. Quantification of skeletal kinetic indices in Paget’s disease using dynamic 18F-fluoride positron emission tomography. J Bone Miner Res 2002;17:854–9.

    Article  CAS  PubMed  Google Scholar 

  46. Pakos EE, Fotopoulos AD, Ioannidis JP. 18F-FDG PET for evaluation of bone marrow infiltration in staging of lymphoma: a meta-analysis. J Nucl Med 2005;46:958–63.

    PubMed  Google Scholar 

  47. Hsu W, Feeley B, Krenek L, Gamradt S, Stout D, Chatziioannou A, et al. The characterization of osteolytic and osteoblastic lesions in a prostate cancer mouse model with the use of 18F-FDG and 18F-fluoride PET/CT scans. In: Transactions of the 51st Annual Meeting of the Orthopaedic Research Society. 2005. Washington DC.

  48. Lee FY, Yu J, Chang SS, Fawwaz R, Parisien MV. Diagnostic value and limitations of fluorine-18 fluorodeoxyglucose positron emission tomography for cartilaginous tumors of bone. J Bone Joint Surg Am 2004;86-A:2677–85.

    PubMed  Google Scholar 

  49. Mumme T, Reinartz P, Alfer J, Muller-Rath R, Buell U, Wirtz DC. Diagnostic values of positron emission tomography versus triple-phase bone scan in hip arthroplasty loosening. Arch Orthop Trauma Surg 2005;125:322–9.

    Article  CAS  PubMed  Google Scholar 

  50. Strauss LG, Dimitrakopoulou-Strauss A, Koczan D, Bernd L, Haberkorn U, Ewerbeck V, et al. 18F-FDG kinetics and gene expression in giant cell tumors. J Nucl Med 2004;45:1528–35.

    CAS  PubMed  Google Scholar 

  51. Eary JF, O'Sullivan F, Powitan Y, Chandhury KR, Vernon C, Bruckner JD, et al. Sarcoma tumor FDG uptake measured by PET and patient outcome: a retrospective analysis. Eur J Nucl Med Mol Imaging 2002;29:1149–54.

    Article  CAS  PubMed  Google Scholar 

  52. Hawkins DS, Schuetze SM, Butrynski JE, Rajendran JG, Vernon CB, Conrad EU 3rd, et al. [18F]Fluorodeoxyglucose positron emission tomography predicts outcome for Ewing sarcoma family of tumors. J Clin Oncol 2005;23:8828–34.

    Article  PubMed  Google Scholar 

  53. O'Sullivan F, Roy S, O'Sullivan J, Vernon C, Eary J. Incorporation of tumor shape into an assessment of spatial heterogeneity for human sarcomas imaged with FDG-PET. Biostatistics 2005;6:293–301.

    Article  PubMed  Google Scholar 

  54. Schuetze SM, Rubin BP, Vernon C, Hawkins DS, Bruckner JD, Conrad EU 3rd, et al. Use of positron emission tomography in localized extremity soft tissue sarcoma treated with neoadjuvant chemotherapy. Cancer 2005;103:339–48.

    Article  PubMed  Google Scholar 

  55. Shields AF, Mankoff DA, Link JM, Graham MM, Eary JF, Kozawa SM, et al. Carbon-11-thymidine and FDG to measure therapy response. J Nucl Med 1998;39:1757–62.

    CAS  PubMed  Google Scholar 

  56. Blokhuis TJ, Patka P, Bakker FC, Haarman HJ, van Lingen A, Roos JC, et al. Quantitative assessment of fracture healing using positron emission tomography. Eur J Nucl Med Mol Imaging 2003;30:329–30.

    Article  PubMed  Google Scholar 

  57. Piert M, Zittel TT, Becker GA, Jahn M, Stahlschmidt A, Maier G, et al. Assessment of porcine bone metabolism by dynamic 18F-fluoride ion PET: correlation with bone histomorphometry. J Nucl Med 2001;42:1091–100.

    CAS  PubMed  Google Scholar 

  58. Messa C, Goodman WG, Hoh CK, Choi Y, Nissenson AR, Salusky IB, et al. Bone metabolic activity measured with positron emission tomography and [18F]fluoride ion in renal osteodystrophy: correlation with bone histomorphometry. J Clin Endocrinol Metab 1993;77:949–55.

    Article  CAS  PubMed  Google Scholar 

  59. Peterson B, Zhang J, Iglesias R, Kabo M, Hedrick M, Benhaim P, et al. Healing of critically sized femoral defects, using genetically modified mesenchymal stem cells from human adipose tissue. Tissue Eng 2005;11:120–9.

    Article  CAS  PubMed  Google Scholar 

  60. Wieland B, Bida G, Padgett H, Go H. Current status of CTI target systems for the production of PET radiochemicals. Proceedings of the 3rd Workshop on Targetry and Target Chemistry; 1989.

  61. Hamacher K, Coenen HH, Stocklin G. Efficient stereospecific synthesis of no-carrier-added 2-[18F]-fluoro-2-deoxy-D-glucose using aminopolyether supported nucleophilic substitution. J Nucl Med 1986;27:235–8.

    CAS  PubMed  Google Scholar 

  62. Stout D, Chow P, Gustilo A, Grubwieser S, Chatziioannou A. Multimodality isolated bed system for mouse imaging experiments. Molecular Imaging and Biology 2003;5:128–29.

    Google Scholar 

  63. Tai YC, Ruangma A, Rowland D, Siegel S, Newport DF, Chow PL, et al. Performance evaluation of the microPET focus: a third-generation microPET scanner dedicated to animal imaging. J Nucl Med 2005;46:455–63.

    PubMed  Google Scholar 

  64. Chatziioannou A, Qi J, Moore A, Annala A, Nguyen K, Leahy R, et al. Comparison of 3-D maximum a posteriori and filtered backprojection algorithms for high-resolution animal imaging with microPET. IEEE Trans Med Imaging 2000;19:507–12.

    Article  CAS  PubMed  Google Scholar 

  65. Loening AM, Gambhir SS. AMIDE: a free software tool for multimodality medical image analysis. Mol Imaging 2003;2:131–7.

    Article  PubMed  Google Scholar 

  66. Whelan DB, Bhandari M, McKee MD, Guyatt GH, Kreder HJ, Stephen D, et al. Interobserver and intraobserver variation in the assessment of the healing of tibial fractures after intramedullary fixation. J Bone Joint Surg Br 2002;84:15–8.

    Article  CAS  PubMed  Google Scholar 

  67. Kokubu T, Hak DJ, Hazelwood SJ, Reddi AH. Development of an atrophic nonunion model and comparison to a closed healing fracture in rat femur. J Orthop Res 2003;21:503–10.

    Article  PubMed  Google Scholar 

  68. Einhorn TA, Majeska RJ, Mohaideen A, Kagel EM, Bouxsein ML, Turek TJ, et al. A single percutaneous injection of recombinant human bone morphogenetic protein-2 accelerates fracture repair. J Bone Joint Surg Am 2003;85-A:1425–35.

    PubMed  Google Scholar 

  69. Frost ML, Cook GJ, Blake GM, Marsden PK, Benatar NA, Fogelman I. A prospective study of risedronate on regional bone metabolism and blood flow at the lumbar spine measured by 18F-fluoride positron emission tomography. J Bone Miner Res 2003;18:2215–22.

    Article  CAS  PubMed  Google Scholar 

  70. Brenner W, Vernon C, Conrad EU, Eary JF. Assessment of the metabolic activity of bone grafts with 18F-fluoride PET. Eur J Nucl Med Mol Imaging 2004;31:1291–8.

    CAS  PubMed  Google Scholar 

  71. dos Santos Neto FL, Volpon JB. Experimental nonunion in dogs. Clin Orthop Relat Res 1984;187:260–71.

    PubMed  Google Scholar 

  72. Volpon JB. Nonunion using a canine model. Arch Orthop Trauma Surg 1994;113:312–7.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, Center for Health Sciences, 76-134, 10833 LeConte Avenue, Los Angeles, CA, 90095, USA

    W. K. Hsu, B. T. Feeley, L. Krenek, D. B. Stout & A. F. Chatziioannou

  2. The Musculoskeletal Institute, Department of Orthopaedic Surgery, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT, 06030-5456, USA

    J. R. Lieberman

Authors
  1. W. K. Hsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B. T. Feeley
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L. Krenek
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D. B. Stout
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. F. Chatziioannou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J. R. Lieberman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. R. Lieberman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hsu, W.K., Feeley, B.T., Krenek, L. et al. The use of 18F-fluoride and 18F-FDG PET scans to assess fracture healing in a rat femur model. Eur J Nucl Med Mol Imaging 34, 1291–1301 (2007). https://doi.org/10.1007/s00259-006-0280-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-006-0280-6

Keywords

Search

Navigation