Skip to main content

Advertisement

SpringerLink
Log in

Imaging of Site Specific Bone Turnover in Osteoporosis Using Positron Emission Tomography

  • Imaging (T Lang and F Wehrli, Section Editors)
  • Published:
Current Osteoporosis Reports Aims and scope Submit manuscript

Abstract

The functional imaging technique of dynamic fluorine-18 labeled sodium fluoride positron emission tomography (18F-NaF PET) allows the quantitative assessment of regional bone formation by measuring the plasma clearance of fluoride to bone at any site in the skeleton. 18F-NaF PET provides a novel and noninvasive method of studying site-specific bone formation at the hip and spine, as well as areas of pure cortical or trabecular bone. The technique complements conventional measurements of bone turnover using biochemical markers and bone biopsy as a tool to investigate new treatments for osteoporosis, and holds promise of a future role as an early biomarker of treatment efficacy in clinical trials. This article reviews methods of acquiring and analyzing 18F-NaF PET scan data, and outlines a simplified approach that uses 5-minute static PET scan images combined with venous blood samples to estimate 18F-NaF plasma clearance at multiple sites in the skeleton with a single injection of tracer.

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.

Institutional subscriptions

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

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Black DM, Cummings SR, Karpf DB, et al. Randomised trial of the effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet. 1996;348:1535–41.

    Article  PubMed  CAS  Google Scholar 

  2. Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the fracture intervention trial. JAMA. 1998;280:2077–82.

    Article  PubMed  CAS  Google Scholar 

  3. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomised clinical trial. JAMA. 1999;282:637–45.

    Article  PubMed  CAS  Google Scholar 

  4. Harris ST, Watts NB, Genant HK, et al. Effects of risedronate treatment on vertebral and non-vertebral fractures in women with postmenopausal osteoporosis. JAMA. 1999;282:1344–52.

    Article  PubMed  CAS  Google Scholar 

  5. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of recombinant human parathyroid hormone (1-34) fragment on spine and non-spine fractures and bone mineral density in postmenopausal osteoporosis. N Engl J Med. 2001;344:1434–41.

    Article  PubMed  CAS  Google Scholar 

  6. Chesnut CH, Skag A, Christiansen C, et al. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res. 2004;19:1241–9.

    Article  CAS  Google Scholar 

  7. Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med. 2004;350:459–68.

    Article  PubMed  CAS  Google Scholar 

  8. Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or stopping alendronate after 5 years of treatment: the fracture intervention trial long-term extension (FLEX): a randomized trial. JAMA. 2006;296:2927–38.

    Article  PubMed  CAS  Google Scholar 

  9. Black DM, Delmas PD, Eastell R, et al. Once-yearly zolendronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356:1809–22.

    Article  PubMed  CAS  Google Scholar 

  10. Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361:756–65.

    Article  PubMed  CAS  Google Scholar 

  11. Eastell R, Nagase S, Small M, et al. Effect of ONO-5334 on bone mineral density and biochemical markers of bone turnover in postmenopausal osteoporosis: 2-year results from the OCEAN study. J Bone Miner Res. 2014;29:458–66.

    Article  PubMed  CAS  Google Scholar 

  12. McClung MR, Grauer A, Boonen S, et al. Romosozumab in postmenopausal women with low bone mineral density. N Engl J Med. 2014;370:412–20.

    Article  PubMed  CAS  Google Scholar 

  13. Garnero P, Weichung JS, Gineyts E, et al. Comparison of new biochemical markers of bone turnover in late postmenopausal osteoporotic women in response to alendronate treatment. J Clin Endocrinol Metab. 1994;79:1693–700.

    PubMed  CAS  Google Scholar 

  14. Glover SJ, Gall M, Schoenborn-Kellenberger O, et al. Establishing a reference interval for bone turnover markers in 637 healthy, young, premenopausal women from the United Kingdom, France, Belgium, and the United States. J Bone Miner Res. 2009;24:389–97.

    Article  PubMed  Google Scholar 

  15. Glover SJ, Eastell R, McCloskey EV, et al. Rapid and robust response of biochemical markers of bone formation to teriparatide therapy. Bone. 2009;45:1053–8.

    Article  PubMed  CAS  Google Scholar 

  16. McClung MR, San Martin J, Miller PD, et al. Opposite bone remodeling effects of teriparatide and alendronate in increasing bone mass. Arch Intern Med. 2005;165:1762–8.

    Article  PubMed  CAS  Google Scholar 

  17. Dempster DW, Cosman F, Kurland ES, et al. Effects of daily treatment with parathyroid hormone on bone microarchitecture and turnover in patients with osteoporosis: a paired biopsy study. J Bone Miner Res. 2001;16:1846–53.

    Article  PubMed  CAS  Google Scholar 

  18. Jiang Y, Zhao JJ, Mitlak BH, et al. Recombinant human parathyroid hormone (1-34) (teriparatide) improves both cortical and cancellous bone structure. J Bone Miner Res. 2003;18:1932–41.

    Article  PubMed  CAS  Google Scholar 

  19. Arlot M, Meunier PJ, Boivin G, et al. Differential effects of teriparatide and alendronate on bone remodeling in postmenopausal women assessed by histomorphometric parameters. J Bone Miner Res. 2005;20:1244–53.

    Article  PubMed  CAS  Google Scholar 

  20. Lindsay R, Zhou H, Cosman F, et al. Effects of a one-month treatment with PTH(1-34) on bone formation on cancellous, endocortical, and periosteal surfaces of the human ilium. J Bone Miner Res. 2007;22:495–502.

    Article  PubMed  CAS  Google Scholar 

  21. Chavassieux P, Meunier PJ, Roux JP, et al. Bone histomorphometry of transiliac paired bone biopsies after 6 or 12 months of treatment with oral strontium ranelate in 387 osteoporotic women. Randomized comparison to alendronate. J Bone Miner Res. 2013.

  22. Reeve J, Wootton R, Hesp B. A new tracer method for the calculation of rates of bone formation and breakdown in osteoporosis and other generalised skeletal disorders. Calcif Tissue Res. 1976;22:191–206.

    Article  PubMed  CAS  Google Scholar 

  23. Reeve J, Arlot ME, Chavassieux PM, et al. The assessment of bone formation and bone resorption in osteoporosis: a comparison between tetracycline-based iliac histomorphometry and whole body 85Sr kinetics. J Bone Miner Res. 1987;2:479–89.

    Article  PubMed  CAS  Google Scholar 

  24. Reeve J, Arlot M, Wootton 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  PubMed  CAS  Google Scholar 

  25. Eastell R, Colwell A, Hampton L, Reeve J. Biochemical markers of bone resorption compared with estimates of bone resorption from radiotracer kinetic studies in osteoporosis. J Bone Miner Res. 1997;12:59–65.

    Article  PubMed  CAS  Google Scholar 

  26. Rowland RE. Radium in humans: a review of US Studies. Argonne National Laboratory, 1994.

  27. Denk E, Hillegonds D, Hurrell RF, et al. Evaluation of 41calcium as a new approach to assess changes in bone metabolism: effect of a bisphosphonate intervention in postmenopausal women with low bone mass. J Bone Miner Res. 2007;22:1518–25.

    Article  PubMed  CAS  Google Scholar 

  28. Lee WH, Wastney ME, Jackson GS, et al. Interpretation of 41Ca data using compartmental modeling in post-menopausal women. Anal Bioanal Chem. 2011;399:1613–22.

    Article  PubMed  CAS  Google Scholar 

  29. Hawkings RA, Choi Y, Huang S-C, et al. Evaluation of the skeletal kinetics of fluorine-18-fluoride ion with PET. J Nucl Med. 1992;33:633–42.

    Google Scholar 

  30. Moore AE, Blake GM, Taylor KA, et al. Assessment of regional changes in skeletal metabolism following 3 and 18 months of teriparatide treatment. J Bone Miner Res. 2010;25:960–7.

    PubMed  CAS  Google Scholar 

  31. Guillemart A, Besnard JC, Le Pape A, Galy G, Fetissoff F. Skeletal uptake of pyrophosphate labeled with technetium-95m and technetium-96, as evaluated by autoradiography. J Nucl Med. 1978;19:895–9.

    PubMed  CAS  Google Scholar 

  32. Schümichen C, Rempfle H, Wagner M, Hoffmann G. The short-term fixation of radiopharmaceuticals in bone. Eur J Nucl Med. 1979;4:423–8.

    Article  PubMed  Google Scholar 

  33. Einhorn TA, Vigorita VJ, Aaron A. Localization of technetium-99m methylene diphosphonate in bone using microautoradiography. J Orthop Res. 1986;4:180–7.

    Article  PubMed  CAS  Google Scholar 

  34. Boivin G, Farlay D, Khebbab MT, Jaurand X, Delmas PD, Meunier PJ. In osteoporotic women treated with strontium ranelate, strontium is located in bone formed during treatment with a maintained degree of mineralization. Osteoporos Int. 2010;21:667–77.

    Article  PubMed  CAS  Google Scholar 

  35. Messa C, Goodman WG, Hoh CK, et al. Bone metabolic activity measured with positron emission tomography and 18F-fluoride ion in renal osteodystrophy: correlation with bone histomorphometry. J Clin Endo Metab. 1993;77:949–55.

    CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  37. Czernin J, Satyamurthy N, Schiepers C. Molecular mechanisms of bone 18F-NaF deposition. J Nucl Med. 2010;51:1826–9.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  38. Siddique M, Blake GM, Frost ML, et al. Estimation of regional bone metabolism from whole-body 18F-fluoride PET static images. Eur J Nucl Med Mol Imaging. 2012;39:337–43. This paper, along with Siddique et al [39••], describes a simplified method of estimating bone plasma clearance from static PET scans.

    Article  PubMed  Google Scholar 

  39. Siddique M, Frost ML, Moore AE, et al. Correcting 18F-fluoride PET static scan measurements of skeletal plasma clearance for tracer efflux from bone. Nucl Med Commun. 2014;35:303–10. Describes a method of correcting the static scan method of Siddique et al [38••] for tracer efflux from bone.

    Article  PubMed  CAS  Google Scholar 

  40. Blake GM, Siddique M, Frost ML, et al. Radionuclide studies of bone metabolism: do bone uptake and bone plasma clearance provide equivalent measurements of bone turnover? Bone. 2011;49:537–42. Discusses the circumstances in which a measurement of bone plasma clearance is a more reliable indicator than SUV of a change in bone turnover.

    Article  PubMed  CAS  Google Scholar 

  41. Fogelman I, Bessent RG, Turner JG, et al. The use of whole-body retention of Tc-99m diphosphonate in the diagnosis of metabolic bone disease. J Nucl Med. 1978;19:270–5.

    PubMed  CAS  Google Scholar 

  42. Brenner W, Bohuslavizki KH, Sieweke N, et al. Quantification of diphosphonate uptake based on conventional bone scanning. Eur J Nucl Med. 1997;24:1284–90.

    Article  PubMed  CAS  Google Scholar 

  43. Keyes JW. SUV: standard uptake or silly useless value? J Nucl Med. 1995;36:1836–9.

    PubMed  Google Scholar 

  44. Blake GM, Moore AE, Fogelman I. Quantitative studies of bone using 99mTc-methylene diphosphonate skeletal plasma clearance. Semin Nucl Med. 2009;39:369–79.

    Article  PubMed  Google Scholar 

  45. Gnanasegaran G, Moore AE, Blake GM, et al. Atypical Paget’s disease with quantitative assessment of tracer kinetics. Clin Nucl Med. 2007;32:765–9.

    Article  PubMed  Google Scholar 

  46. Blake GM, Zivanovic MA, McEwan AJ, Ackery DM. 89Sr therapy: strontium kinetics in disseminated carcinoma of the prostate. Eur J Nucl Med. 1986;12:447–54.

    PubMed  CAS  Google Scholar 

  47. Al-Beyatti Y, Siddique M, Frost ML, et al. Precision of 18F-fluoride PET skeletal kinetic studies in the assessment of bone metabolism. Osteoporos Int. 2012;23:2535–41. Reports precision data for measurements of SUV and bone plasma clearance measured using the Hawkins compartmental model and the Patlak plot.

    Article  PubMed  CAS  Google Scholar 

  48. Grant FD, Fahey FH, Packard AB, et al. Skeletal PET with 18F-Fluoride: applying new technology to an old tracer. J Nucl Med. 2008;49:68–78.

    Article  PubMed  Google Scholar 

  49. Li Y, Schiepers C, Lake R, et al. Clinical utility of 18F-fluoride PET/CT in benign and malignant bone diseases. Bone. 2012;50:128–39.

    Article  PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  51. Taves DR. Electrophoretic mobility of serum fluoride. Nature. 1968;220:582–3.

    Article  PubMed  CAS  Google Scholar 

  52. Hyldstrup L, McNair P, Ring P, Henriksen O. Studies on diphosphonate kinetics. Part I: evaluation of plasma elimination curves during 24 hours. Eur J Nucl Med. 1987;12:581–4.

    Article  PubMed  CAS  Google Scholar 

  53. Moore AE, Hain SF, Blake GM, Fogelman I. Validation of ultrafiltration as a method of measuring free 99mTc-MDP. J Nucl Med. 2003;44:891–7.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  55. Cook GJ, Lodge MA, Marsden PK, et al. Noninvasive assessment of skeletal kinetics using fluorine-18 fluoride positron emission tomography: evaluation of image and population-derived arterial input functions. Eur J Nucl Med. 1999;26:1424–9.

    Article  PubMed  CAS  Google Scholar 

  56. Piert M, Machulla HJ, Jahn M, et al. Coupling of porcine bone blood flow and metabolism in high-turnover bone disease measured by [15O]H2O and [18F]fluoride ion positron emission tomography. Eur J Nucl Med Mol Imaging. 2002;29:907–14.

    Article  PubMed  CAS  Google Scholar 

  57. Frost ML, Cook GJR, Blake GM, et al. 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  PubMed  CAS  Google Scholar 

  58. Installe J, Nzeusseu A, Bol A, et al. 18F-fluoride PET for monitoring therapeutic response in Paget's disease of bone. J Nucl Med. 2005;46:1650–8.

    PubMed  CAS  Google Scholar 

  59. Frost ML, Blake GM, Cook GJ, et al. Differences in regional bone perfusion and turnover between lumbar spine and distal humerus: 18F-fluoride PET study of treatment-naïve and treated postmenopausal women. Bone. 2009;45:942–8.

    Article  PubMed  Google Scholar 

  60. Doot RK, Muzi M, Peterson LM, et al. Kinetic analysis of 18F-fluoride PET images of breast cancer bone metastases. J Nucl Med. 2010;51:521–7.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  61. Frost ML, Siddique M, Blake GM, et al. Differential effects of teriparatide on regional bone formation using 18F-fluoride positron emission tomography. J Bone Miner Res. 2011;26:1002–11. First assessment of the effect of teriparatide on bone plasma clearance measurements in the lumbar spine and comparison with SUV measurements in the hip.

    Article  PubMed  CAS  Google Scholar 

  62. Frost ML, Siddique M, Blake GM, et al. Regional bone metabolism at the lumbar spine and hip following discontinuation of alendronate and risedronate treatment in postmenopausal women. Osteoporos Int. 2012;23:2107–16.

    Article  PubMed  CAS  Google Scholar 

  63. Frost ML, Moore AE, Siddique M, et al. 18F-fluoride PET as a noninvasive imaging biomarker for determining treatment efficacy of bone active agents at the hip: a prospective, randomized, controlled clinical study. J Bone Miner Res. 2013;28:1337–47. First assessment of the effect of teriparatide on bone plasma clearance measurements at different sites in the proximal femur.

    Article  PubMed  CAS  Google Scholar 

  64. Frost ML, Compston JE, Goldsmith D, et al. 18F-fluoride positron emission tomography measurements of regional bone formation in hemodialysis patients with suspected adynamic bone disease. Calcif Tissue Int. 2013;93:436–47.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  65. Muzi M, O’Sullivan F, Mankoff D, et al. Quantitative assessment of dynamic PET imaging data on cancer imaging. Magn Reson Imaging. 2012;30:1203–15. Useful discussion of the advantages of PET measurements of plasma clearance for the assessment of tumor tracer kinetics.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Puri T, Blake GM, Siddique M, et al. Validation of new image-derived arterial input functions at the aorta using 18F-fluoride positron emission tomography. Nucl Med Commun. 2011;32:486–95.

    Article  PubMed  Google Scholar 

  67. Puri T, Blake GM, Frost ML, et al. Validation of image-derived arterial input functions at the femoral artery using 18F-fluoride positron emission tomography. Nucl Med Commun. 2011;32:808–17.

    Article  PubMed  Google Scholar 

  68. Blake GM, Siddique M, Puri T, et al. A semipopulation input function for quantifying static and dynamic 18F-fluoride PET scans. Nucl Med Commun. 2012;33:881–8. Reports a simple method of assessing the arterial input function for use with the static scan method of evaluating bone plasma clearance [38••, 39••].

    Article  PubMed  Google Scholar 

  69. Wootton R, Doré C. The single-passage extraction of 18F in rabbit bone. Clin Phys Physiol Meas. 1986;7:333–43.

    Article  PubMed  CAS  Google Scholar 

  70. Piert M, Zittel TT, Machulla HJ, et al. Blood flow measurements with 15OH2O and 18F-fluoride ion PET in porcine vertebrae. J Bone Miner Res. 1998;13:1328–36.

    Article  PubMed  CAS  Google Scholar 

  71. Siddique M, Frost ML, Blake GM, et al. The precision and sensitivity of 18F-fluoride PET for measuring regional bone metabolism: a comparison of quantification methods. J Nucl Med. 2011;52:1748–55. Compares the precision and sensitivity of nine different methods of quantifying 18F-NaF dynamic scans.

    Article  PubMed  Google Scholar 

  72. Holden JE, Doudet D, Endres CJ, et al. Graphical analysis of 6-fluoro-L-dopa trapping: effect of inhibition of catechol-O-methyltransferase. J Nucl Med. 1997;38:1568–74.

    PubMed  CAS  Google Scholar 

  73. Blake GM, Siddique M, Frost ML, et al. Quantitative PET imaging using 18F sodium fluoride in the assessment of metabolic bone diseases and the monitoring of their response to therapy. PET Clin. 2012;7:275–91.

    Article  Google Scholar 

  74. Uchida K, Nakajima H, Miyazaki T, et al. Effects of alendronate on bone metabolism in glucocorticoid-induced osteoporosis measured by 18F-fluoride PET: a prospective study. J Nucl Med. 2009;50:1808–14.

    Article  PubMed  CAS  Google Scholar 

  75. Chesnut 4th CH, Chesnut 3rd CH. Can PET-CT imaging and radiokinetic analyses provide useful clinical information on atypical femoral shaft fracture in osteoporotic patients? Curr Osteoporos Rep. 2012;10:42–7.

    Article  PubMed  Google Scholar 

Download references

Conflict of Interest

G. M. Blake, M. Siddique, M. L. Frost, A. E. B. Moore, and I. Fogelman have all received research grants from Novartis, Eli Lilly, and Warner Chilcott.

Human and Animal Rights and Informed Consent

All studies by the authors involving animal and/or human subjects were performed after approval by the appropriate institutional review boards. When required, written informed consent was obtained from all participants.

Author information

Authors and Affiliations

  1. Osteoporosis Research Unit, King’s College London, Guy’s Campus, London, SE1 9RT, UK

    Glen M. Blake, Michelle L. Frost & Amelia E. B. Moore

  2. King’s College London, Clinical PET Centre, St Thomas’ Campus, London, UK

    Musib Siddique

  3. Nuclear Medicine Department, King’s College London, Guy’s Campus, London, UK

    Ignac Fogelman

Authors
  1. Glen M. Blake
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Musib Siddique
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michelle L. Frost
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Amelia E. B. Moore
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ignac Fogelman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Glen M. Blake.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Blake, G.M., Siddique, M., Frost, M.L. et al. Imaging of Site Specific Bone Turnover in Osteoporosis Using Positron Emission Tomography. Curr Osteoporos Rep 12, 475–485 (2014). https://doi.org/10.1007/s11914-014-0231-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11914-014-0231-2

Keywords

Search

Navigation