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Current Osteoporosis Reports
Published in: Current Osteoporosis Reports 4/2014

01-12-2014 | Imaging (T Lang and F Wehrli, Section Editors)

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

Authors: Glen M. Blake, Musib Siddique, Michelle L. Frost, Amelia E. B. Moore, Ignac Fogelman

Published in: Current Osteoporosis Reports | Issue 4/2014

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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.
Literature
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.CrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.
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
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
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.PubMedCrossRef
33.
Einhorn TA, Vigorita VJ, Aaron A. Localization of technetium-99m methylene diphosphonate in bone using microautoradiography. J Orthop Res. 1986;4:180–7.PubMedCrossRef
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.PubMedCrossRef
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.
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
37.
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. PubMedCrossRef
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. PubMedCrossRef
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. PubMedCrossRef
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
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.PubMedCrossRef
43.
Keyes JW. SUV: standard uptake or silly useless value? J Nucl Med. 1995;36:1836–9.PubMed
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.PubMedCrossRef
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.PubMedCrossRef
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
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. PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
50.
Blau M, Nagler W, Bender MA. Fluorine-18: a new isotope for bone scanning. J Nucl Med. 1962;3:332–4.PubMed
51.
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.PubMedCrossRef
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
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
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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
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.PubMedCrossRef
60.
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. PubMedCrossRef
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.PubMedCrossRef
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. PubMedCrossRef
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.PubMedCrossRefPubMedCentral
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. PubMedCrossRefPubMedCentral
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.PubMedCrossRef
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.PubMedCrossRef
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••].PubMedCrossRef
69.
Wootton R, Doré C. The single-passage extraction of 18F in rabbit bone. Clin Phys Physiol Meas. 1986;7:333–43.PubMedCrossRef
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.PubMedCrossRef
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. PubMedCrossRef
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
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.CrossRef
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.PubMedCrossRef
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.PubMedCrossRef
Metadata
Title
Imaging of Site Specific Bone Turnover in Osteoporosis Using Positron Emission Tomography
Authors
Glen M. Blake
Musib Siddique
Michelle L. Frost
Amelia E. B. Moore
Ignac Fogelman
Publication date
01-12-2014
Publisher
Springer US
Published in
Current Osteoporosis Reports / Issue 4/2014
Print ISSN: 1544-1873
Electronic ISSN: 1544-2241
DOI
https://doi.org/10.1007/s11914-014-0231-2

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