- Email: [email protected]
MR-based trabecular bone microstructure is not altered in subjects with indolent systemic mastocytosis
Clinical Imaging xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Clinical Imaging journal homepage: http://www.clinicalimaging.org
MR-based trabecular bone microstructure is not altered in subjects with indolent systemic mastocytosis☆ Thomas Baum a,⁎, Dimitrios C. Karampinos a, Knut Brockow b, Vanadin Seifert-Klauss c, Pia M. Jungmann a, Tilo Biedermann b, Ernst J. Rummeny a, Jan S. Bauer d, Dirk Müller a,e a
Institut für Radiologie, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 München, Germany Klinik für Dermatologie und Allergologie am Biederstein, Technische Universität München, Biedersteiner Str. 29, 80802 München, Germany Frauenklinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 München, Germany d Abteilung für Neuroradiologie, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 München, Germany e Institut und Poliklinik für Diagnostische Radiologie, Universitätsklinikum Köln, Kerpener Str. 62, 50937 Köln, Germany b c
a r t i c l e
i n f o
Article history: Received 5 November 2014 Received in revised form 30 November 2014 Accepted 8 December 2014 Available online xxxx Keywords: Indolent systemic mastocytosis Osteoporosis Magnetic resonance imaging Trabecular bone microstructure
a b s t r a c t Subjects with indolent systemic mastocytosis (ISM) have an increased risk for osteoporosis. It has been demonstrated that trabecular bone microstructure analysis improves the prediction of bone strength beyond dual-energy X-ray absorptiometry-based bone mineral density. The purpose of this study was to obtain Magnetic Resonance (MR)-based trabecular bone microstructure parameters as advanced imaging biomarkers in subjects with ISM (n=18) and compare them with those of normal controls (n=18). Trabecular bone microstructure parameters were not significantly (PN .05) different between subjects with ISM and controls. These findings revealed important pathophysiological information about ISM-associated osteoporosis and may limit the use of trabecular bone microstructure analysis in this clinical setting. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Mastocytosis is a neoplastic disease involving mast cells and their CD34+ progenitors [1]. A prevalence of mastocytosis of 1:10.000 has been reported, but underdiagnosis is assumed [2]. Systemic mastocytosis (SM) is defined by the presence of abnormal mast cells in extracutaneous organs including the bone marrow [3]. SM is grouped into four variants: indolent systemic mastocytosis (ISM), SM with an associated clonal nonmast cell lineage disease, aggressive SM, and mast cell leukaemia. ISM is the most common variant of SM comprising about two thirds of all cases and involving mainly skin and bone marrow. Importantly, subjects with ISM have an increased risk for osteoporosis, even in those under the age of 50 [4,5]. Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing an individual to an increased risk of fracture [6]. Osteoporotic fractures considerably reduce healthrelated quality of life and are associated with an increased mortality [7,8]. The assessment of osteoporosis associated fracture risk has traditionally been based on the assessment of bone mineral density (BMD) at the spine and hip by using dual-energy X-ray absorptiometry (DXA) [9]. However, more than 50% of peripheral osteoporotic fractures occur
☆ Conflict of Interest: The authors state no conflict of interest. ⁎ Corresponding author. Institut für Radiologie, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 München, Germany. Tel.: +49-894140-2621; fax: +49-89-4140-4834. E-mail address: [email protected] (T. Baum).
in subjects with BMD values not yet in the osteoporotic range [10]. Therefore, it would be beneficial to establish early imaging biomarkers which could support clinicians in their treatment decision to prevent ISM-associated bone loss, for example, as shown for zoledronic acid [11]. High-resolution imaging techniques including high-resolution peripheral quantitative computed tomography (hr-pQCT), multidetector computed tomography (MDCT), and magnetic resonance imaging (MRI) allow for an assessment of trabecular bone microstructure as advanced imaging biomarkers [12]. Trabecular bone microstructure parameters have shown to improve the prediction of bone strength beyond DXA-based BMD [13]. MRI is advantageous compared to hr-pQCT and MDCT, since it does not expose subjects to ionizing radiation. MR-based assessment of trabecular bone microstructure has mostly been performed at the peripheral skeleton, since it is challenging at the proximal femur and not possible at the spine. Therefore, the purpose of the present study was to obtain MR-based trabecular bone microstructure parameters at the distal radius in subjects with ISM and to compare them with those of normal controls.
2. Materials and methods 2.1. Subjects The study was approved by the institutional ethics committee for human research. All subjects gave written informed consent before participation in the study.
http://dx.doi.org/10.1016/j.clinimag.2014.12.006 0899-7071/© 2014 Elsevier Inc. All rights reserved.
Please cite this article as: Baum T, et al, MR-based trabecular bone microstructure is not altered in subjects with indolent systemic mastocytosis, Clin Imaging (2014), http://dx.doi.org/10.1016/j.clinimag.2014.12.006
2
T. Baum et al. / Clinical Imaging xxx (2014) xxx–xxx
The diagnosis of ISM was made according to current guidelines of the World Health Organization (WHO) [3]. Exclusion criteria were any other hematological or metabolic bone disorders. Eighteen subjects with ISM (13 females, 5 males, 47±11 years of age) and a current DXA examination of the spine and hip were included in this study. The serum tryptase levels of subjects with ISM amounted to 56.6± 40.3 μg/l. Furthermore, 18 young, healthy subjects (13 females, 5 males, 24±2 years of age) were included as controls. No DXA measurements were available in the control cohort, since these measurements were not clinically indicated and therefore not approved by the institutional ethics committee for human research due to the radiation exposure. All subjects had no history of fragility fractures. 2.2. MRI The left distal radius of all subjects was scanned by using a 1.5T MR system (Philips Achieva, Eindhoven, the Netherlands) and a fourchannel wrist coil (Medical Advances, Milwaukee, WI, USA). Subjects were positioned supine with the left forearm adjacent to the body and parallel to the magnet bore axis. Scout images in transverse, coronal, and sagittal planes were used for the planning of a 3D gradient echo sequence (TE of 6.7 ms, TR of 23.8 ms, flip angle of 20°, matrix of 512×512, field of view of 100 mm, in-plane resolution of 195×195 μm 2, axial slice thickness of 500 μm). Sixty axial sections covering a range of 3.0 cm were acquired starting at the most proximal part of the distal joint line, avoiding the area directly adjacent to the subchondral bone. The acquisition time amounted to 7:16 min.
parameters were calculated in the segmented trabecular bone compartment in analogy to standard histomorphometry using the mean intercept length method [16]: bone fraction (bone volume divided by total volume, BF=BV/TV), trabecular number [TbN; (mm − 1)], trabecular separation [TbSp; (mm)], and trabecular thickness [TbTh; (mm)]. Parameters were labeled as apparent (app.) values, since they could not depict the true trabecular bone microstructure due to the limited spatial resolution. Furthermore, fractal dimension (FD) as texture measurement of the trabecular bone microstructure was determined in the MR images using a box counting algorithm as previously described [14]. Reproducibility errors for these trabecular bone microstructure measurements were reported previously and ranged from 0.69% to 4.94% [14]. 2.4. Statistical analysis The statistical analyses were performed with Statistical Package for the Social Sciences (SPSS) (SPSS, Chicago, IL, USA) using a two-sided 0.05 level of significance. The Kolmogorov–Smirnov test showed no significant difference from a normal distribution for most parameters (PN .05). Therefore, trabecular bone microstructure parameters of the subjects with ISM and normal controls were compared with t tests. Additional adjustment for age by using multiple, logistic regression models did not change the P values. Thus, only the P values of the t tests are reported in the results section. All values are represented as mean±standard deviation. The associations of bone microstructure parameters, DXA-based T- and Z-scores, and serum tryptase levels of subjects with ISM were determined with Pearson correlation coefficients r.
2.3. MR image analysis 3. Results MR images of the distal radii were transferred to a remote LINUX workstation. The distal radius was segmented using a fully automated, in-house developed seeded growing algorithm as previously described [14]. Thus, the whole trabecular bone compartment excluding the cortical shell was segmented (Fig. 1). Binarization of the MR images was required to calculate morphometric parameters of trabecular bone microstructure. For this purpose, a dual threshold algorithm was applied as outlined by Majumdar et al. [15]. Four morphometric
The averaged DXA T- and Z-scores of subjects with ISM amounted to − 1.6±1.2 and − 1.1±1.0, respectively. According to the DXAbased 2001 WHO definition, 3 subjects with ISM were classified as osteoporotic (T-scoreb−2.5), 10 subject as osteopenic (− 1.0≤T-scoreb −2.5), and 5 subjects as having normal BMD (T-scoreN−1.0). DXA measurements of male and female subjects with ISM were not significantly different (PN.05).
Fig. 1. Example of an MR image of the distal radius of a 44-year-old female with ISM (left side) and the corresponding segmentation of the trabecular bone compartment color coded in red (right side).
Please cite this article as: Baum T, et al, MR-based trabecular bone microstructure is not altered in subjects with indolent systemic mastocytosis, Clin Imaging (2014), http://dx.doi.org/10.1016/j.clinimag.2014.12.006
T. Baum et al. / Clinical Imaging xxx (2014) xxx–xxx Table 1 Trabecular bone microstructure parameters in controls and subjects with ISM
app.BF app.TbN (mm−1) app.TbSp (mm) app.TbTh (mm) FD
Subjects with ISM (n=18)
Controls (n=18)
P value
0.37±0.03 1.53±0.09 0.42±0.04 0.24±0.02 1.64±0.04
0.37±0.03 1.50±0.11 0.43±0.05 0.25±0.02 1.65±0.05
.956 .506 .354 .616 .294
Differences were evaluated with t tests and were not statistically significant (PN.05).
Differences between subjects with ISM and controls were not statistically significant for app.BF (0.37±0.03 vs. 0.37±±0.03, P=.956), app.TbN (1.53±0.09 mm−1 vs. 1.50±0.11 mm −1, P=.506), app.TbSp (0.42±0.04 mm vs. 0.43±0.05 mm, P= .354), app.TbTh (0.24±0.02 mm vs. 0.25±0.02 mm, P= .616), and FD (1.64±0.04 vs. 1.65±0.05, P=.294) (Table 1, Fig. 2). No significant correlations were observed between bone microstructure parameters and DXA-based T- and Z-scores of subjects with ISM (PN .05). Furthermore, age and serum tryptase levels of the subjects with ISM showed no significant correlations (PN.05) with DXA- and MR-based measurements.
4. Discussion No alterations in the trabecular bone microstructure at the distal radius were observed in subjects with ISM compared to normal controls. Furthermore, the trabecular bone microstructure parameters were not associated with the DXA status and the serum tryptase levels of subjects with ISM. Subjects with ISM have a high prevalence of osteoporosis and associated fragility fractures [5]. DXA-based BMD values are most commonly used by clinicians in their treatment decision to preserve ISM associated bone loss, for example, by zoledronic acid prescription [11]. T-scores relate the individual BMD to a 30-year old healthy cohort of the same sex, while Z-scores give the relationship with the subject's own age group. Z-Scores have been suggested for younger age groups with high risk of osteoporosis, for example, anorexic young women or breast
3
cancer patients with aromatase inhibitor treatment. In both groups, suggestions have been made to intervene with osteoporosis-specific medication at or below a threshold Z-score of −2.0. Rossini et al. also suggested using DXA-based Z-score instead of T-score in order to define intervention thresholds in subjects with ISM [17]. Furthermore, the MastFx score has been introduced that distinguishes subjects with ISM at high, intermediate, and low risk of new fragility fractures [18]. The parameters included in the MastFx score were sex, serum Type I collagen C-telopeptide, hip BMD, urticaria pigmentosa, and alcohol intake. In our study, we investigated the effects of ISM on trabecular bone microstructure and the potential benefits of trabecular bone microstructure as early imaging biomarker for ISM-associated osteoporosis, since bone strength has been named to reflect the integration of BMD and bone microstructure. Clinical MRI systems are broadly available and allow for noninvasive assessment of trabecular bone microstructure at the peripheral skeleton [13]. MRI is advantageous compared to hrpQCT and MDCT, since it does not expose patients to ionizing radiation. MR-based trabecular bone microstructure analysis at the distal radius has been previously shown to improve the prediction of radial bone strength beyond DXA-based BMD [19,20]. Furthermore, assessment of MR-based trabecular bone microstructure significantly improved the diagnostic performance in differentiating subjects with and without osteoporotic vertebral fractures [21]. MR-based trabecular bone microstructure measurements are known to be reproducible as reported previously (0.69% to 4.94% at 1.5T) [14]. No significant differences in bone microstructure parameters were observed in subjects with ISM compared to normal controls. The findings suggest that initial ISM-associated bone loss is not preceded by the deterioration of trabecular bone microstructure, at least at peripheral sites such as the distal radius. ISM may affect bone microstructure locally at various sites, and the radius may not have been affected in the same way as in subjects with systemic generalized osteoporosis. Thus, the use of trabecular bone microstructure analysis as diagnostic biomarker in this clinical setting might be limited. This is an important finding, since trabecular bone microstructure analysis has been shown to be useful in the assessment of bone strength beyond BMD measurements in the context of osteoporosis [12,13]. Furthermore, it is important to note that serum tryptase levels are not a reasonable biomarker
Fig. 2. Boxplots of app. BF, TbN, TbSp, TbTh, and FD in controls and subjects with ISM. Differences between the two groups were not statistically significant (PN.05).
Please cite this article as: Baum T, et al, MR-based trabecular bone microstructure is not altered in subjects with indolent systemic mastocytosis, Clin Imaging (2014), http://dx.doi.org/10.1016/j.clinimag.2014.12.006
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T. Baum et al. / Clinical Imaging xxx (2014) xxx–xxx
for osteoporosis in our study population of subjects with ISM, since we observed no correlation with DXA measurements. Therefore, a study is warranted investigating the trabecular bone microstructure of central skeletal sites (i.e., spine and proximal femur) to rule out an anatomic dependency of trabecular bone microstructure changes in subjects with ISM. However, MR-based assessment of trabecular bone microstructure is challenging at the proximal femur and not possible at the spine. Thus, this issue can only be investigated by using high-resolution MDCT with its considerable radiation exposure. This study has several limitations. Due to their young age in the midtwenties, the control group may not yet have attained neither their peak bone mass nor their peak bone microstructure parameters. As the ISM group was also relatively young, their decline in structural parameters may not have been substantial enough for differences to reach significance in these small numbers. Furthermore, not having DXA measurements for the control group is a limitation in this study, and it may have been better to choose an older cohort with DXA ordered for other reasons for the control group. However, it appears that this would be unlikely to change the obtained results. The cross-sectional design is a further limitation of the present study. To enhance our knowledge about the deterioration of trabecular bone microstructure in relation to DXA-based BMD loss in subjects with ISM, a longitudinal study would be needed in the future. In conclusion, changes of the trabecular bone microstructure at the distal radius were not observed in subjects with ISM compared to normal controls. These findings reveal important pathophysiological information about ISM-associated osteoporosis and may limit the use of trabecular bone microstructure analysis as diagnostic biomarker in this clinical setting. Future studies with longitudinal study design would be needed to investigate this issue in more detail. Acknowledgments This work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG BA 4085/2-1 and BA 4906/1-1). References [1] Horny HP, Sotlar K, Valent P. Mastocytosis: state of the art. Pathobiology 2007;74(2):121–32. [2] Brockow K. Epidemiology, prognosis, and risk factors in mastocytosis. Immunol Allergy Clin North Am 2014;34(2):283–95. [3] Valent P, Akin C, Escribano L, Fodinger M, Hartmann K, Brockow K, Castells M, Sperr WR, Kluin-Nelemans HC, Hamdy NA, Lortholary O, Robyn J, van DJ, Sotlar K, Hauswirth AW, Arock M, Hermine O, Hellmann A, Triggiani M, Niedoszytko M, Schwartz LB, Orfao A, Horny HP, Metcalfe DD. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Invest 2007;37(6):435–53.
[4] Rossini M, Zanotti R, Viapiana O, Tripi G, Orsolini G, Idolazzi L, Bonadonna P, Schena D, Escribano L, Adami S, Gatti D. Bone involvement and osteoporosis in mastocytosis. Immunol Allergy Clin North Am 2014;34(2):383–96. [5] van der Veer E, van der Goot W, de Monchy JG, Kluin-Nelemans HC, van Doormaal JJ. High prevalence of fractures and osteoporosis in patients with indolent systemic mastocytosis. Allergy 2012;67(3):431–8. [6] NIH. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy, March 7–29, 2000: highlights of the conference. South Med J 2001;94(6): 569–73. [7] Hallberg I, Bachrach-Lindstrom M, Hammerby S, Toss G, Ek AC. Health-related quality of life after vertebral or hip fracture: a seven-year follow-up study. BMC Musculoskelet Disord 2009;10:135. [8] Ioannidis G, Papaioannou A, Hopman WM, Akhtar-Danesh N, Anastassiades T, Pickard L, Kennedy CC, Prior JC, Olszynski WP, Davison KS, Goltzman D, Thabane L, Gafni A, Papadimitropoulos EA, Brown JP, Josse RG, Hanley DA, Adachi JD. Relation between fractures and mortality: results from the Canadian Multicentre Osteoporosis Study. CMAJ 2009;181(5):265–71. [9] Blake GM, Fogelman I. An update on dual-energy x-ray absorptiometry. Semin Nucl Med 2010;40(1):62–73. [10] Schuit SC, van der Klift M, Weel AE, de Laet CE, Burger H, Seeman E, Hofman A, Uitterlinden AG, van Leeuwen JP, Pols HA. Fracture incidence and association with bone mineral density in elderly men and women: the Rotterdam Study. Bone 2004;34(1):195–202. [11] Rossini M, Zanotti R, Viapiana O, Tripi G, Idolazzi L, Biondan M, Orsolini G, Bonadonna P, Adami S, Gatti D. Zoledronic acid in osteoporosis secondary to mastocytosis. Am J Med 2014;127(11):1127 e1-4. [12] Link TM. Osteoporosis imaging: state of the art and advanced imaging. Radiology 2012;263(1):3–17. [13] Baum T, Karampinos DC, Liebl H, Rummeny EJ, Waldt S, Bauer JS. High-resolution bone imaging for osteoporosis diagnostics and therapy monitoring using clinical MDCT and MRI. Curr Med Chem 2013;20(38):4844–52. [14] Baum T, Dutsch Y, Muller D, Monetti R, Sidorenko I, Rath C, Rummeny EJ, Link TM, Bauer JS. Reproducibility of trabecular bone structure measurements of the distal radius at 1.5 and 3.0T magnetic resonance imaging. J Comput Assist Tomogr 2012; 36(5):623–6. [15] Majumdar S, Genant HK, Grampp S, Newitt DC, Truong VH, Lin JC, Mathur A. Correlation of trabecular bone structure with age, bone mineral density, and osteoporotic status: in vivo studies in the distal radius using high resolution magnetic resonance imaging. J Bone Miner Res 1997;12(1):111–8. [16] Parfitt AM, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, Ott SM, Recker RR. Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res 1987;2(6):595–610. [17] Rossini M, Zanotti R, Bonadonna P, Artuso A, Caruso B, Schena D, Vecchiato D, Bonifacio M, Viapiana O, Gatti D, Senna G, Riccio A, Passalacqua G, Pizzolo G, Adami S. Bone mineral density, bone turnover markers and fractures in patients with indolent systemic mastocytosis. Bone 2011;49(4):880–5. [18] van der Veer E, Arends S, van der Hoek S, Versluijs JB, de Monchy JG, Oude Elberink JN, van Doormaal JJ. Predictors of new fragility fractures after diagnosis of indolent systemic mastocytosis. J Allergy Clin Immunol 2014;134(6):1413–21. [19] Hudelmaier M, Kollstedt A, Lochmuller EM, Kuhn V, Eckstein F, Link TM. Gender differences in trabecular bone architecture of the distal radius assessed with magnetic resonance imaging and implications for mechanical competence. Osteoporos Int 2005;16(9):1124–33. [20] Baum T, Kutscher M, Muller D, Rath C, Eckstein F, Lochmuller EM, Rummeny EJ, Link TM, Bauer JS. Cortical and trabecular bone structure analysis at the distal radiusprediction of biomechanical strength by DXA and MRI. J Bone Miner Metab 2013; 31(2):212–21. [21] Mueller D, Link TM, Monetti R, Bauer J, Boehm H, Seifert-Klauss V, Rummeny EJ, Morfill GE, Raeth C. The 3D-based scaling index algorithm: a new structure measure to analyze trabecular bone architecture in high-resolution MR images in vivo. Osteoporos Int 2006;17(10):1483–93.
Please cite this article as: Baum T, et al, MR-based trabecular bone microstructure is not altered in subjects with indolent systemic mastocytosis, Clin Imaging (2014), http://dx.doi.org/10.1016/j.clinimag.2014.12.006
Contents lists available at ScienceDirect
Clinical Imaging journal homepage: http://www.clinicalimaging.org
MR-based trabecular bone microstructure is not altered in subjects with indolent systemic mastocytosis☆ Thomas Baum a,⁎, Dimitrios C. Karampinos a, Knut Brockow b, Vanadin Seifert-Klauss c, Pia M. Jungmann a, Tilo Biedermann b, Ernst J. Rummeny a, Jan S. Bauer d, Dirk Müller a,e a
Institut für Radiologie, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 München, Germany Klinik für Dermatologie und Allergologie am Biederstein, Technische Universität München, Biedersteiner Str. 29, 80802 München, Germany Frauenklinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 München, Germany d Abteilung für Neuroradiologie, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 München, Germany e Institut und Poliklinik für Diagnostische Radiologie, Universitätsklinikum Köln, Kerpener Str. 62, 50937 Köln, Germany b c
a r t i c l e
i n f o
Article history: Received 5 November 2014 Received in revised form 30 November 2014 Accepted 8 December 2014 Available online xxxx Keywords: Indolent systemic mastocytosis Osteoporosis Magnetic resonance imaging Trabecular bone microstructure
a b s t r a c t Subjects with indolent systemic mastocytosis (ISM) have an increased risk for osteoporosis. It has been demonstrated that trabecular bone microstructure analysis improves the prediction of bone strength beyond dual-energy X-ray absorptiometry-based bone mineral density. The purpose of this study was to obtain Magnetic Resonance (MR)-based trabecular bone microstructure parameters as advanced imaging biomarkers in subjects with ISM (n=18) and compare them with those of normal controls (n=18). Trabecular bone microstructure parameters were not significantly (PN .05) different between subjects with ISM and controls. These findings revealed important pathophysiological information about ISM-associated osteoporosis and may limit the use of trabecular bone microstructure analysis in this clinical setting. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Mastocytosis is a neoplastic disease involving mast cells and their CD34+ progenitors [1]. A prevalence of mastocytosis of 1:10.000 has been reported, but underdiagnosis is assumed [2]. Systemic mastocytosis (SM) is defined by the presence of abnormal mast cells in extracutaneous organs including the bone marrow [3]. SM is grouped into four variants: indolent systemic mastocytosis (ISM), SM with an associated clonal nonmast cell lineage disease, aggressive SM, and mast cell leukaemia. ISM is the most common variant of SM comprising about two thirds of all cases and involving mainly skin and bone marrow. Importantly, subjects with ISM have an increased risk for osteoporosis, even in those under the age of 50 [4,5]. Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing an individual to an increased risk of fracture [6]. Osteoporotic fractures considerably reduce healthrelated quality of life and are associated with an increased mortality [7,8]. The assessment of osteoporosis associated fracture risk has traditionally been based on the assessment of bone mineral density (BMD) at the spine and hip by using dual-energy X-ray absorptiometry (DXA) [9]. However, more than 50% of peripheral osteoporotic fractures occur
☆ Conflict of Interest: The authors state no conflict of interest. ⁎ Corresponding author. Institut für Radiologie, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 München, Germany. Tel.: +49-894140-2621; fax: +49-89-4140-4834. E-mail address: [email protected] (T. Baum).
in subjects with BMD values not yet in the osteoporotic range [10]. Therefore, it would be beneficial to establish early imaging biomarkers which could support clinicians in their treatment decision to prevent ISM-associated bone loss, for example, as shown for zoledronic acid [11]. High-resolution imaging techniques including high-resolution peripheral quantitative computed tomography (hr-pQCT), multidetector computed tomography (MDCT), and magnetic resonance imaging (MRI) allow for an assessment of trabecular bone microstructure as advanced imaging biomarkers [12]. Trabecular bone microstructure parameters have shown to improve the prediction of bone strength beyond DXA-based BMD [13]. MRI is advantageous compared to hr-pQCT and MDCT, since it does not expose subjects to ionizing radiation. MR-based assessment of trabecular bone microstructure has mostly been performed at the peripheral skeleton, since it is challenging at the proximal femur and not possible at the spine. Therefore, the purpose of the present study was to obtain MR-based trabecular bone microstructure parameters at the distal radius in subjects with ISM and to compare them with those of normal controls.
2. Materials and methods 2.1. Subjects The study was approved by the institutional ethics committee for human research. All subjects gave written informed consent before participation in the study.
http://dx.doi.org/10.1016/j.clinimag.2014.12.006 0899-7071/© 2014 Elsevier Inc. All rights reserved.
Please cite this article as: Baum T, et al, MR-based trabecular bone microstructure is not altered in subjects with indolent systemic mastocytosis, Clin Imaging (2014), http://dx.doi.org/10.1016/j.clinimag.2014.12.006
2
T. Baum et al. / Clinical Imaging xxx (2014) xxx–xxx
The diagnosis of ISM was made according to current guidelines of the World Health Organization (WHO) [3]. Exclusion criteria were any other hematological or metabolic bone disorders. Eighteen subjects with ISM (13 females, 5 males, 47±11 years of age) and a current DXA examination of the spine and hip were included in this study. The serum tryptase levels of subjects with ISM amounted to 56.6± 40.3 μg/l. Furthermore, 18 young, healthy subjects (13 females, 5 males, 24±2 years of age) were included as controls. No DXA measurements were available in the control cohort, since these measurements were not clinically indicated and therefore not approved by the institutional ethics committee for human research due to the radiation exposure. All subjects had no history of fragility fractures. 2.2. MRI The left distal radius of all subjects was scanned by using a 1.5T MR system (Philips Achieva, Eindhoven, the Netherlands) and a fourchannel wrist coil (Medical Advances, Milwaukee, WI, USA). Subjects were positioned supine with the left forearm adjacent to the body and parallel to the magnet bore axis. Scout images in transverse, coronal, and sagittal planes were used for the planning of a 3D gradient echo sequence (TE of 6.7 ms, TR of 23.8 ms, flip angle of 20°, matrix of 512×512, field of view of 100 mm, in-plane resolution of 195×195 μm 2, axial slice thickness of 500 μm). Sixty axial sections covering a range of 3.0 cm were acquired starting at the most proximal part of the distal joint line, avoiding the area directly adjacent to the subchondral bone. The acquisition time amounted to 7:16 min.
parameters were calculated in the segmented trabecular bone compartment in analogy to standard histomorphometry using the mean intercept length method [16]: bone fraction (bone volume divided by total volume, BF=BV/TV), trabecular number [TbN; (mm − 1)], trabecular separation [TbSp; (mm)], and trabecular thickness [TbTh; (mm)]. Parameters were labeled as apparent (app.) values, since they could not depict the true trabecular bone microstructure due to the limited spatial resolution. Furthermore, fractal dimension (FD) as texture measurement of the trabecular bone microstructure was determined in the MR images using a box counting algorithm as previously described [14]. Reproducibility errors for these trabecular bone microstructure measurements were reported previously and ranged from 0.69% to 4.94% [14]. 2.4. Statistical analysis The statistical analyses were performed with Statistical Package for the Social Sciences (SPSS) (SPSS, Chicago, IL, USA) using a two-sided 0.05 level of significance. The Kolmogorov–Smirnov test showed no significant difference from a normal distribution for most parameters (PN .05). Therefore, trabecular bone microstructure parameters of the subjects with ISM and normal controls were compared with t tests. Additional adjustment for age by using multiple, logistic regression models did not change the P values. Thus, only the P values of the t tests are reported in the results section. All values are represented as mean±standard deviation. The associations of bone microstructure parameters, DXA-based T- and Z-scores, and serum tryptase levels of subjects with ISM were determined with Pearson correlation coefficients r.
2.3. MR image analysis 3. Results MR images of the distal radii were transferred to a remote LINUX workstation. The distal radius was segmented using a fully automated, in-house developed seeded growing algorithm as previously described [14]. Thus, the whole trabecular bone compartment excluding the cortical shell was segmented (Fig. 1). Binarization of the MR images was required to calculate morphometric parameters of trabecular bone microstructure. For this purpose, a dual threshold algorithm was applied as outlined by Majumdar et al. [15]. Four morphometric
The averaged DXA T- and Z-scores of subjects with ISM amounted to − 1.6±1.2 and − 1.1±1.0, respectively. According to the DXAbased 2001 WHO definition, 3 subjects with ISM were classified as osteoporotic (T-scoreb−2.5), 10 subject as osteopenic (− 1.0≤T-scoreb −2.5), and 5 subjects as having normal BMD (T-scoreN−1.0). DXA measurements of male and female subjects with ISM were not significantly different (PN.05).
Fig. 1. Example of an MR image of the distal radius of a 44-year-old female with ISM (left side) and the corresponding segmentation of the trabecular bone compartment color coded in red (right side).
Please cite this article as: Baum T, et al, MR-based trabecular bone microstructure is not altered in subjects with indolent systemic mastocytosis, Clin Imaging (2014), http://dx.doi.org/10.1016/j.clinimag.2014.12.006
T. Baum et al. / Clinical Imaging xxx (2014) xxx–xxx Table 1 Trabecular bone microstructure parameters in controls and subjects with ISM
app.BF app.TbN (mm−1) app.TbSp (mm) app.TbTh (mm) FD
Subjects with ISM (n=18)
Controls (n=18)
P value
0.37±0.03 1.53±0.09 0.42±0.04 0.24±0.02 1.64±0.04
0.37±0.03 1.50±0.11 0.43±0.05 0.25±0.02 1.65±0.05
.956 .506 .354 .616 .294
Differences were evaluated with t tests and were not statistically significant (PN.05).
Differences between subjects with ISM and controls were not statistically significant for app.BF (0.37±0.03 vs. 0.37±±0.03, P=.956), app.TbN (1.53±0.09 mm−1 vs. 1.50±0.11 mm −1, P=.506), app.TbSp (0.42±0.04 mm vs. 0.43±0.05 mm, P= .354), app.TbTh (0.24±0.02 mm vs. 0.25±0.02 mm, P= .616), and FD (1.64±0.04 vs. 1.65±0.05, P=.294) (Table 1, Fig. 2). No significant correlations were observed between bone microstructure parameters and DXA-based T- and Z-scores of subjects with ISM (PN .05). Furthermore, age and serum tryptase levels of the subjects with ISM showed no significant correlations (PN.05) with DXA- and MR-based measurements.
4. Discussion No alterations in the trabecular bone microstructure at the distal radius were observed in subjects with ISM compared to normal controls. Furthermore, the trabecular bone microstructure parameters were not associated with the DXA status and the serum tryptase levels of subjects with ISM. Subjects with ISM have a high prevalence of osteoporosis and associated fragility fractures [5]. DXA-based BMD values are most commonly used by clinicians in their treatment decision to preserve ISM associated bone loss, for example, by zoledronic acid prescription [11]. T-scores relate the individual BMD to a 30-year old healthy cohort of the same sex, while Z-scores give the relationship with the subject's own age group. Z-Scores have been suggested for younger age groups with high risk of osteoporosis, for example, anorexic young women or breast
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cancer patients with aromatase inhibitor treatment. In both groups, suggestions have been made to intervene with osteoporosis-specific medication at or below a threshold Z-score of −2.0. Rossini et al. also suggested using DXA-based Z-score instead of T-score in order to define intervention thresholds in subjects with ISM [17]. Furthermore, the MastFx score has been introduced that distinguishes subjects with ISM at high, intermediate, and low risk of new fragility fractures [18]. The parameters included in the MastFx score were sex, serum Type I collagen C-telopeptide, hip BMD, urticaria pigmentosa, and alcohol intake. In our study, we investigated the effects of ISM on trabecular bone microstructure and the potential benefits of trabecular bone microstructure as early imaging biomarker for ISM-associated osteoporosis, since bone strength has been named to reflect the integration of BMD and bone microstructure. Clinical MRI systems are broadly available and allow for noninvasive assessment of trabecular bone microstructure at the peripheral skeleton [13]. MRI is advantageous compared to hrpQCT and MDCT, since it does not expose patients to ionizing radiation. MR-based trabecular bone microstructure analysis at the distal radius has been previously shown to improve the prediction of radial bone strength beyond DXA-based BMD [19,20]. Furthermore, assessment of MR-based trabecular bone microstructure significantly improved the diagnostic performance in differentiating subjects with and without osteoporotic vertebral fractures [21]. MR-based trabecular bone microstructure measurements are known to be reproducible as reported previously (0.69% to 4.94% at 1.5T) [14]. No significant differences in bone microstructure parameters were observed in subjects with ISM compared to normal controls. The findings suggest that initial ISM-associated bone loss is not preceded by the deterioration of trabecular bone microstructure, at least at peripheral sites such as the distal radius. ISM may affect bone microstructure locally at various sites, and the radius may not have been affected in the same way as in subjects with systemic generalized osteoporosis. Thus, the use of trabecular bone microstructure analysis as diagnostic biomarker in this clinical setting might be limited. This is an important finding, since trabecular bone microstructure analysis has been shown to be useful in the assessment of bone strength beyond BMD measurements in the context of osteoporosis [12,13]. Furthermore, it is important to note that serum tryptase levels are not a reasonable biomarker
Fig. 2. Boxplots of app. BF, TbN, TbSp, TbTh, and FD in controls and subjects with ISM. Differences between the two groups were not statistically significant (PN.05).
Please cite this article as: Baum T, et al, MR-based trabecular bone microstructure is not altered in subjects with indolent systemic mastocytosis, Clin Imaging (2014), http://dx.doi.org/10.1016/j.clinimag.2014.12.006
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for osteoporosis in our study population of subjects with ISM, since we observed no correlation with DXA measurements. Therefore, a study is warranted investigating the trabecular bone microstructure of central skeletal sites (i.e., spine and proximal femur) to rule out an anatomic dependency of trabecular bone microstructure changes in subjects with ISM. However, MR-based assessment of trabecular bone microstructure is challenging at the proximal femur and not possible at the spine. Thus, this issue can only be investigated by using high-resolution MDCT with its considerable radiation exposure. This study has several limitations. Due to their young age in the midtwenties, the control group may not yet have attained neither their peak bone mass nor their peak bone microstructure parameters. As the ISM group was also relatively young, their decline in structural parameters may not have been substantial enough for differences to reach significance in these small numbers. Furthermore, not having DXA measurements for the control group is a limitation in this study, and it may have been better to choose an older cohort with DXA ordered for other reasons for the control group. However, it appears that this would be unlikely to change the obtained results. The cross-sectional design is a further limitation of the present study. To enhance our knowledge about the deterioration of trabecular bone microstructure in relation to DXA-based BMD loss in subjects with ISM, a longitudinal study would be needed in the future. In conclusion, changes of the trabecular bone microstructure at the distal radius were not observed in subjects with ISM compared to normal controls. These findings reveal important pathophysiological information about ISM-associated osteoporosis and may limit the use of trabecular bone microstructure analysis as diagnostic biomarker in this clinical setting. Future studies with longitudinal study design would be needed to investigate this issue in more detail. Acknowledgments This work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG BA 4085/2-1 and BA 4906/1-1). References [1] Horny HP, Sotlar K, Valent P. Mastocytosis: state of the art. Pathobiology 2007;74(2):121–32. [2] Brockow K. Epidemiology, prognosis, and risk factors in mastocytosis. Immunol Allergy Clin North Am 2014;34(2):283–95. [3] Valent P, Akin C, Escribano L, Fodinger M, Hartmann K, Brockow K, Castells M, Sperr WR, Kluin-Nelemans HC, Hamdy NA, Lortholary O, Robyn J, van DJ, Sotlar K, Hauswirth AW, Arock M, Hermine O, Hellmann A, Triggiani M, Niedoszytko M, Schwartz LB, Orfao A, Horny HP, Metcalfe DD. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Invest 2007;37(6):435–53.
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Please cite this article as: Baum T, et al, MR-based trabecular bone microstructure is not altered in subjects with indolent systemic mastocytosis, Clin Imaging (2014), http://dx.doi.org/10.1016/j.clinimag.2014.12.006