¹⁸F-sodium fluoride bone deposition quantitation with PET in Mice: Variation with age, sex, and circadian rhythm

Abstract

Aim The aim of this study was to establish a data base for normal ¹⁸F-sodium fluoride (¹⁸F-NaF) bone uptake as a function of age, sex and circadian rhythm in mice.

Methods In 12 female (F) and 12 male (M) C57BL/6N mice PET images were acquired 90 min after intravenous injection of 20 MBq ¹⁸F-NaF for 30 minutes. Each mouse was imaged in follow-up studies at 1, 3, 6, 13 and 21 months of age. In order to assess for physiologic changes related to circadian rhythm, animals were imaged during light (sleep phase) as well as during night conditions (awake phase). Bone uptake is described as the median percentage of the injected activity (%IA) and in relation to bone volume (%IA/ml).

Results A significant smaller bone volume was found in F (1.79 ml) compared to M (1.99 ml; p < 0.001). In sex-pooled data, highest bone uptake occurred at an age of 1 month (61.1 %IA, 44.5 %IA/ml) with a significant reduction (p < 0.001) at age 3 months (43.6 %IA, 23.6 %IA/ml), followed by an increase between 13 (47.3 %IA, 24.5 %IA/ml) and 21 months (52.2 %IA, 28.1 %IA/ml). F had a significantly higher total uptake (F 48.2 %IA, M 43.8 %IA; p = 0.026) as well as a higher uptake per ml bone tissue (F 27.0 %IA/ml; M 22.4 %IA/ml; p < 0.001). A significant impact of circadian rhythm was only found for F at ages of 3 and 6 months with a higher uptake during the sleep phase.

Conclusion Circadian rhythm had a significant impact on uptake only in F of 3 and 6 months. Regarding sex, F showed generally higher uptake rates than M. The highest uptake values were observed during bone growth at age 1 month in both sexes, a second uptake peak occurred in elderly F. Designing future bone uptake studies with M, attention must be paid to age only, while in F circadian rhythm and age must be taken into account.

Zusammenfassung

Ziel Ziel dieser Studie war die Etablierung von Normwerten für den Knochen-Uptake von ¹⁸F-Natruimfluorid (¹⁸F-NaF) in Abhängigkeit von Alter, Geschlecht und zirkadianem Rhythmus.

Methoden Bei 12 weiblichen (F) und 12 männlichen (M) C57BL/6N-Mäusen wurde 90 min nach intravenöser Injektion von 20 MBq eine ¹⁸F-NaF-PET-Untersuchungen von 30 min Dauer durchgeführt. Jede Maus wurde mit 1, 3, 6, 13 und 21 Monaten im Verlauf untersucht. Um physiologische Veränderungen in Bezug auf den zirkadianen Rhythmus zu erfassen, wurden die Untersuchungen während der Hellphase (Schlafphase) sowie der Dunkelphase (Wachphase) durchgeführt. Der Knochen-Uptake ist als medianer Prozentwert der injizierten Aktivität (%IA) und in Relation zum Knochenvolumen (%IA/ml) aufgeführt.

Ergebnisse F (1,79 ml) zeigten ein signifikant kleineres Knochenvolumen als M (1,99ml; p < 0,001). Der höchste Knochen-Uptake fand sich bei beiden Geschlechtern im Alter von 1 Monat (61,1 %IA, 44,5 %IA/ml) mit einem signifikanten Abfall (p < 0,001) mit 3 Monaten (43,6 %IA, 23,6 %IA/ml), gefolgt von einem Anstieg zwischen 13 (47,3 %IA, 24,5 %IA/ml) und 21 Monaten (52,2 %IA, 28,1 %IA/ml). F zeigten sowohl einen signifikant höheren Gesamt-Uptake (F 48,2 %IA, M 43,8 %IA; p = 0,026) als auch einen höheren Uptake je ml Knochengewebe (F 27,0 %IA/ml; M 22,4 %IA/ml; p < 0,001). Nur bei F im Alter von 3 und 6 Monaten zeigte sich ein signifikanter Einfluss der Tageszeit mit einem höheren Uptake während der Schlafphase.

Schlussfolgerung Ein signifikanter Einfluss des zirkadianen Rhythmus zeigte sich nur bei F im Alter von 3 und 6 Monaten. Generell hatten F einen höheren Uptake als M. Während des Knochenwachstums im Alter von 1 Monat hatten beide Geschlechter den höchsten Uptake, mit einem zweiten Anstieg bei alten F. Folglich müssen beim Design von Studien bezüglich des Knochen-Uptakes bei M das Alter und bei F der zirkadiane Rhythmus sowie das Alter als Einflussfaktoren berücksichtigt werden.

Key words

bone - ¹⁸F-fluoride - PET - sex - circadian rhythm - age - mouse

Schlüsselwörter

Knochen - ¹⁸F-Natriumfluorid - PET - Geschlecht - circadianer Rhythmus - Alter - Maus

^* current address: Department of Internal Medicine, Military Hospital Hamburg, Germany.

Publication History

Received: 11 May 2020

Accepted: 18 June 2020

Article published online:
16 July 2020

• References

• 1 Adesanya O, Sprowson A, Masters J. et al. Review of the role of dynamic 18F-NaF PET in diagnosing and distinguishing between septic and aseptic loosening in hip prosthesis. Journal of orthopaedic surgery and research 2015; 10: 5
• 2 Bastawrous S, Bhargava P, Behnia F. et al. Newer PET application with an old tracer: role of 18F-NaF skeletal PET/CT in oncologic practice. Radiographics 2014; 34: 1295-1316
• 3 Beheshti M, Mottaghy F, Payche F. et al. 18F-NaF PET/CT: EANM procedure guidelines for bone imaging. European journal of nuclear medicine and molecular imaging 2015; 42: 1767-1777
• 4 Beindorff N, Bartelheimer A, Huang K. et al. Normal Values of Thyroid Uptake of 99mTechnetium Pertechnetate SPECT in Mice with Respect to Age, Sex, and Circadian Rhythm. Nuklearmedizin 2018; 57: 181-189
• 5 Berding G, Schliephake H, van den Hoff J. et al. Assessment of the incorporation of revascularized fibula grafts used for mandibular reconstruction with F-18-PET. Nuklearmedizin 2001; 40: 51-58
• 6 Berger F, Lee YP, Loening AM. et al. Whole-body skeletal imaging in mice utilizing microPET: optimization of reproducibility and applications in animal models of bone disease. European journal of nuclear medicine and molecular imaging 2002; 29: 1225-1236
• 7 Blahd WH. Benedict Cassen The Father of Body Organ Imaging. Cancer biotherapy & radiopharmaceuticals 2000; 15: 423-429
• 8 Blake GM, Frost ML, Fogelman I. Quantitative radionuclide studies of bone. J Nucl Med 2009; 50: 1747-1750
• 9 Blake GM, Park-Holohan SJ, Cook GJ. et al Quantitative studies of bone with the use of 18F-fluoride and 99mTc-methylene diphosphonate. Seminars in nuclear medicine 2001
• 10 Blau M, Ganatra R, Bender MA. 18F-fluoride for bone imaging. Seminars in nuclear medicine 1972
• 11 Blau M, Nagler W, Bender M. Fluorine-18: a new isotope for bone scanning. J Nuclear Med 1962; 3: 332-334
• 12 Brenner W, Bohuslavizki KH, Sieweke N. et al. Quantification of diphosphonate uptake based on conventional bone scanning. Eur J Nucl Med 1997; 24: 1284-1290
• 13 Brenner W, Sieweke N, Bohuslavizki KH. et al. Age- and sex-related bone uptake of Tc-99m-HDP measured by whole-body bone scanning. Nuklearmedizin 2000; 39: 127-132
• 14 Brenner W, Vernon C, Muzi M. et al. Comparison of different quantitative approaches to 18F-fluoride PET scans. Journal of Nuclear Medicine 2004; 45: 1493-1500
• 15 Chakraborty D, Bhattacharya A, Mete UK. et al. Comparison of 18F fluoride PET/CT and 99mTc-MDP bone scan in the detection of skeletal metastases in urinary bladder carcinoma. Clinical nuclear medicine 2013; 38: 616-621
• 16 Charkes ND, Brookes M, Makler Jr PT. 18 Studies of Skeletal Tracer Kinetics: II. Evaluation of a Five-Compartment Model of. J Nucl Med 1979; 20: 1150-1157
• 17 Czernin J, Satyamurthy N, Schiepers C. Molecular mechanisms of bone 18F-NaF deposition. Journal of Nuclear Medicine 2010; 51: 1826-1829
• 18 Davis MA, Jones AG. Comparison of 99mTc-labeled phosphate and phosphonate agents for skeletal imaging. Seminars in nuclear medicine 1976
• 19 Dudek M, Meng QJ. Running on time: the role of circadian clocks in the musculoskeletal system. Biochem J 2014; 463: 1-8
• 20 Dyke DV, Anger HO, Yano Y. et al. Bone blood flow shown with F18 and the positron camera. American Journal of Physiology-Legacy Content 1965; 209: 65-70
• 21 Eastell R, Delmas PD, Hodgson SF. et al. Bone formation rate in older normal women: concurrent assessment with bone histomorphometry, calcium kinetics, and biochemical markers. J Clin Endocrinol Metab 1988; 67: 741-748
• 22 Even-Sapir E, Metser U, Flusser G. 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. Journal of Nuclear Medicine 2004; 45: 272-278
• 23 Even-Sapir E, Mishani E, Flusser G. et al 18F-Fluoride positron emission tomography and positron emission tomography/computed tomography. Seminars in nuclear medicine 2007
• 24 Felicio LS, Nelson JF, Finch CE. Longitudinal studies of estrous cyclicity in aging C57BL/6J mice: II. Cessation of cyclicity and the duration of persistent vaginal cornification. Biol Reprod 1984; 31: 446-453
• 25 Flammersfeld R. Über den circadianen Profiferationsrhythmus in der proximalen Tibiametaphyse bei der jungen Ratte während der enchondralen Ossifikation [Inaugural-Dissertation]. Bochum: Ruhr-Universität; 1988
• 26 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: 270-275
• 27 Frost ML, Blake GM, Park-Holohan SJ. et al. Long-term precision of 18F-fluoride PET skeletal kinetic studies in the assessment of bone metabolism. Journal of Nuclear Medicine 2008; 49: 700-707
• 28 Gosden RG, Laing SC, Felicio LS. et al. Imminent oocyte exhaustion and reduced follicular recruitment mark the transition to acyclicity in aging C57BL/6J mice. Biol Reprod 1983; 28: 255-260
• 29 Grant FD, Fahey FH, Packard AB. et al. Skeletal PET with 18F-fluoride: applying new technology to an old tracer. Journal of nuclear medicine 2008; 49: 68-78
• 30 Grynpas MD. Fluoride effects on bone crystals. Journal of Bone and Mineral Research 1990; 5: S169-S175
• 31 Halloran BP, Ferguson VL, Simske SJ. et al. Changes in bone structure and mass with advancing age in the male C57BL/6J mouse. Journal of bone and mineral research 2002; 17: 1044-1050
• 32 Hillner BE, Siegel BA, Hanna L. et al. Impact of 18F-fluoride PET in patients with known prostate cancer: initial results from the National Oncologic PET Registry. Journal of Nuclear Medicine 2014; 55: 574-581
• 33 Hillner BE, Siegel BA, Hanna L. et al. Impact of 18F-fluoride PET on intended management of patients with cancers other than prostate cancer: results from the National Oncologic PET Registry. Journal of Nuclear Medicine 2014; 55: 1054-1061
• 34 Holmes RA. Quantification of skeletal Tc-99m labeled phosphates to defect metabolic bone disease. J Nucl Med 1978; 19: 330-331
• 35 Hsu WK, Virk MS, Feeley BT. et al. Characterization of osteolytic, osteoblastic, and mixed lesions in a prostate cancer mouse model using 18F-FDG and 18F-fluoride PET/CT. Journal of Nuclear Medicine 2008; 49: 414-421
• 36 Huang K, Lukas M, Steffen IG. et al. Normal Values of Renal Function measured with 99mTechnetium Mercaptoacetyltriglycine SPECT in Mice with Respect to Age, Sex and Circadian Rhythm. Nuklearmedizin 2018; 57: 224-233
• 37 Irmler IM, Gebhardt P, Hoffmann B. et al. 18F-Fluoride positron emission tomography/computed tomography for noninvasive in vivo quantification of pathophysiological bone metabolism in experimental murine arthritis. Arthritis research & therapy 2014; 16: R155
• 38 Kulshrestha RK, Vinjamuri S, England A. et al. The role of 18F-sodium fluoride PET/CT bone scans in the diagnosis of metastatic bone disease from breast and prostate cancer. Journal of nuclear medicine technology 2016; 44: 217-222
• 39 Nahmias C, Cockshott WP, Belbeck L. et al. Measurement of absolute bone blood flow by positron emission tomography. Skeletal radiology 1986; 1: 198-200
• 40 Nelson JF, Felicio LS, Randall PK. et al. A longitudinal study of estrous cyclicity in aging C57BL/6J mice: I. Cycle frequency, length and vaginal cytology. Biol Reprod 1982; 27: 327-339
• 41 Ovadia D, Metser U, Lievshitz G. et al. Back pain in adolescents: assessment with integrated 18F-fluoride positron-emission tomography-computed tomography. Journal of Pediatric Orthopaedics 2007; 27: 90-93
• 42 Park-Holohan SJ, Blake G, Fogelman I. Quantitative studies of bone using 18F-fluoride and 99mTc-methylene diphosphonate: evaluation of renal and whole-blood kinetics. Nuclear medicine communications 2001; 22: 1037-1044
• 43 Piert M, Zittel TT, Becker GA. et al. Assessment of porcine bone metabolism by dynamic [18F] fluoride ion PET: correlation with bone histomorphometry. Journal of Nuclear Medicine 2001; 4: 1091-1100
• 44 Prisby RD. Mechanical, hormonal and metabolic influences on blood vessels, blood flow and bone. J Endocrinol 2017; 235: R77-R10
• 45 Prisby RD, Dominguez 2nd JM, Muller-Delp J. et al. Aging and estrogen status: a possible endothelium-dependent vascular coupling mechanism in bone remodeling. PLoS One 2012; 7: e48564
• 46 Roche B, Vanden-Bossche A, Malaval L. et al. Parathyroid hormone 1–84 targets bone vascular structure and perfusion in mice: impacts of its administration regimen and of ovariectomy. J Bone Miner Res 2014; 29: 1608-1618
• 47 Roche B, Vanden-Bossche A, Normand M. et al. Validated Laser Doppler protocol for measurement of mouse bone blood perfusion – response to age or ovariectomy differs with genetic background. Bone 2013; 55: 418-426
• 48 Schiepers C, Nuyts J, Bormans G. et al. Fluoride kinetics of the axial skeleton measured in vivo with fluorine-18-fluoride PET. Journal of Nuclear Medicine 1997; 38: 1970-1976
• 49 Schirrmeister H, Glatting G, Hetzel J. et al. Prospective evaluation of the clinical value of planar bone scans, SPECT, and 18F-labeled NaF PET in newly diagnosed lung cancer. Journal of Nuclear Medicine 2001; 42: 1800-1804
• 50 Schliephake H, Berding G, Knapp W. et al. Monitoring of graft perfusion and osteoblast activity in revascularised fibula segments using [18F]‐positron emission tmomography. International Journal of Oral & Maxillofacial Surgery 1999; 28: 349-355
• 51 Schnöckel U, Reuter S, Stegger L. et al. Dynamic 18F-fluoride small animal PET to noninvasively assess renal function in rats. European journal of nuclear medicine and molecular imaging 2008; 35: 2267-2274
• 52 Segall G, Delbeke D, Stabin MG. et al. SNM practice guideline for sodium 18F-fluoride PET/CT bone scans 1.0. Journal of Nuclear Medicine 2010; 51: 1813-1820
• 53 Simmons DJ, Nichols Jr G. Diurnal periodicity in the metabolic activity of bone tissue. Am J Physiol 1966; 210: 411-418
• 54 Subramanian G, McAfee J. A New Complex of 99mTc for Skeletal Imaqinq. Radiology 1971; 99: 192-196
• 55 Ter-Pogossian MM, Phelps ME, Hoffman EJ. et al. A positron-emission transaxial tomograph for nuclear imaging (PETT). Radiology 1975; 114: 89-98
• 56 Townsend DW. Dual-modality imaging: combining anatomy and function. Journal of Nuclear Medicine 2008; 49: 938-955
• 57 Weber D, Greenberg E, Dimich A. et al Kinetics of radionuclides used for bone studies. Sloan-Kettering Inst. for Cancer Research, New York. Memorial and James … 1969
• 58 Wong KK, Piert M. Dynamic bone imaging with 99mTc-labeled diphosphonates and 18F-NaF: mechanisms and applications. Journal of Nuclear Medicine 2013; 54: 590-599
• 59 Wootton R. The single-passage extraction of 18F in rabbit bone. Clinical Science 1974; 47: 73-77