PET/CT & SPECT/CT IN BENIGN BONE DISEASE WOUTER VAN DER BRUGGEN
PET/CT & SPECT/CT IN BENIGN BONE DISEASE Wouter van der Bruggen
Dit proefschrift is goedgekeurd door: Promotor prof. dr. L.F. de Geus - Oei, Universiteit Twente, Leids Universitair Medisch Centrum, Technische Universiteit Delft Co-promotoren dr. N.M. Appelman - Dijkstra, Leids Universitair Medisch Centrum dr. D. Vriens, Leids Universitair Medisch Centrum Printed by Ipskamp Printing | proefschriften.net Layout and cover design: Harma Makken, persoonlijkproefschrift.nl ISBN (print): 978-90-365-5864-8 ISBN (digital): 978-90-365-5865-5 URL: https://doi.org/10.3990/1.9789036558655 © 2023 Wouter van der Bruggen, The Netherlands. All rights reserved. No parts of this thesis may be reproduced, stored in a retrieval system or transmitted in any form or by any means without permission of the author. Alle rechten voorbehouden. Niets uit deze uitgave mag worden vermenigvuldigd, in enige vorm of op enige wijze, zonder voorafgaande schriftelijke toestemming van de auteur.
PET/CT & SPECT/CT IN BENIGN BONE DISEASE PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Universiteit Twente, op gezag van de rector magnificus, prof. dr. ir. A. Veldkamp, volgens besluit van het College voor Promoties in het openbaar te verdedigen op woensdag 6 december 2023 om 12.45 uur door Wouter van der Bruggen geboren op 22 maart 1977 in Steenwijk, Nederland
PROMOTIE COMMISSIE: Voorzitter / secretaris: prof.dr. J.L. Herek Promotor: prof. dr. L.F. de Geus - Oei Universiteit Twente, Leids Universitair Medisch Centrum, Technische Universiteit Delft Co-promotoren: dr. N.M. Appelman - Dijkstra Leids Universitair Medisch Centrum dr. D. Vriens Leids Universitair Medisch Centrum Leden: prof. dr. R.H.J.A. Slart Universiteit Twente, TNW, Biomedical Photonic Imaging prof. dr. D.B.F. Saris Universiteit Twente, TNW, Developmental BioEngineering prof. dr. A.W.J.M. Glaudemans UMCG Groningen prof. dr. W.F. Lems AUMC Amsterdam dr. L. Heijmen Leids Universitair Medisch Centrum dr. M.S. Velema Slingeland Ziekenhuis, Doetinchem The writing and printing of this thesis were accomplished without any funding or other financial support.
Voor Arnoud en Rosalie
Contents GENERAL INTRODUCTION and OUTLINE of THIS THESIS Chapter 1 General introduction and outline of this thesis 10 PART I OVERVIEW of MOLECULAR IMAGING in BONE DISEASES & BONE-SPECT/CT of the EXTREMITIES Chapter 2 The EANM practice guidelines for bone scintigraphy. 28 Eur J Nucl Med Mol Imaging. 2016 Aug;43(9):1723-38. Chapter 3 SPECT/CT in the Postoperative Painful Knee. 62 Semin Nucl Med. 2018 Sep;48(5):439-453. Chapter 4 SPECT/CT in Postoperative Hand and Wrist Pain. 94 Semin Nucl Med. 2018 Sep;48(5):396-409. Chapter 5 Review of the role of bone-SPECT/CT in tarsal coalitions. 120 Nucl Med Commun. 2023 Feb 1;44(2):115-130. PART II QUANTIFYING SKELETAL BURDEN in FIBROUS DYSPLASIA using SODIUM FLUORIDE PET/CT Chapter 6 Quantifying skeletal burden in fibrous dysplasia using sodium fluoride PET/CT. 150 Eur J Nucl Med Mol Imaging. 2020;47(6):1527‐1537. Chapter 7 Considerations on bone volume normalization in quantifying skeletal burden in fibrous dysplasia using sodium fluoride PET/CT. (letter to the editor) 174 Eur J Nucl Med Mol Imaging. 2020 Jun;47(6):1351-1352.
Chapter 8 Denosumab reduces lesional Fluoride skeletal burden on Na[18F]F PET-CT in patients with Fibrous Dysplasia/ McCune-Albright syndrome. 180 J Clin Endocrinol Metab. 2021 Jul 13;106(8):e2980-e2994. Chapter 9 Regression of fibrous dysplasia in response to denosumab therapy: a report of two cases. 206 Bone Rep. 2021 Apr 9;14:101058. GENERAL DISCUSSION and SUMMARY Chapter 10 General discussion and future perspectives 224 Chapter 11 Summary of this thesis 246 Chapter 12 Nederlandse samenvatting 254 APPENDICES List of publications 266 Acknowledgements / Dankwoord 272 Curriculum vitae 282
GENERAL INTRODUCTION AND OUTLINE OF THIS THESIS
We’ve all got stardust in our bones - Ben Harper
CHAPTER 1 General introduction and outline of this thesis
12 Chapter 1 General introduction Benign bone and joint disease: scope of this thesis Benign bone and joint diseases are a heterogeneous range of diseases, including degenerative, infectious and inflammatory, metabolic, congenital, traumatic, and iatrogenic origin. The general practitioner, orthopedic surgeon, trauma surgeon, endocrinologist, rheumatologist, radiologist and nuclear medicine physician, have an interest in one or more of these pathologies. Besides history taking and physical examination, imaging has acquired a central role in the diagnosis and follow-up of many of these diseases. Osteoarthritis is the most prevalent bone disease and may affect any joint in the body. Knee degenerative joint disease is responsible for almost 80% of the burden of osteoarthritis worldwide . Although age is an important contributing risk factor for osteoarthritis, not only elderly are affected by degenerative joint disease. For example, tarsal coalition is a common congenital cause of foot pain in adolescents due to an abnormal connection of two or more of the bones linking the hind- and midfoot. It may cause pain in the affected joint in adolescents and young adults, as well as secondary osteoarthritis in adjacent joints before the fourth decade. Fibrous Dysplasia / McCune Albright Syndrome (FD/MAS), in contrast, is a rare benign metabolic bone diseases which may affect one or multiple bones anywhere in the skeleton, leading to a broad variety of clinical manifestations. This thesis studied the (potential) role of specific molecular and multimodality imaging in three groups of patients with benign bone and joint disease: 1. severe osteoarthritis of selected joints of the extremities (i.e., knee, hand and wrist) in evaluation for unexplained pain after surgery 2. tarsal coalition at primary diagnosis after plain radiographs and during follow-up after surgery 3. FD/MAS before and after treatment with bone remodeling therapy Osteoarthritis, extent of the problem Bone and joint diseases lead to high burden on individuals, health and social-care systems and its negative effect on disability-adjusted life-years (DALY’s) is growing faster than most non-communicable diseases [2, 3]. To illustrate the impact of bone and joint diseases, in the Netherlands, in 2020, an estimated 40,900 people were newly diagnosed with osteoarthritis of the knee by the general practitioner (15,400 men, 25,500 women) and in total over 746,000 Dutch citizens had knee osteoarthritis, making it the most prevalent form of osteoarthritis . For our country, in 2019 the
13 General introduction and outline of this thesis osteoarthritis-related costs for needed care was 1.1 billion euros, being 1.1% of total healthcare expenditure [5, 6]. The extent of the clinical and socio-economic burden frommusculoskeletal disease as a whole is, in short, substantial. Not every patient with (suspected) osteoarthritis will need medical imaging. In more challenging cases, however, for example in preparation of or in follow-up after orthopaedic surgical intervention for severe osteoarthritis (such as total knee arthroplasty, wrist surgery), or in painful tarsal coalition, medical imaging techniques will often play a central role. Patients with osteoarthritis of the knee, hand, and wrist and patients with tarsal coalitions under careful consideration for surgery, were studied in Part I of this thesis. In this setting, considerable potential costs for society are at stake as surgery is an expensive intervention. Studying the (potential) role of early accurate non-invasive medical imaging may aid in facilitating optimal and cost-effective care. Limitations in imaging benign peri-operative bone and joint disease of the extremities Although total knee arthroplasty in patients with (severe) osteoarthritis is mostly very successful, a considerable number of patients will experience persisting pain complaints, with an estimated 15-year failure of 7% [7, 8]. Persisting pain after knee surgery may have many different causes, one of the most notorious causes being loosening of the prosthesis material, with the consequence of possible revisional surgery at stake. Plain radiographs lack the sensitivity to adequately detect (aseptic) prosthesis loosening and are also less suitable for imaging three-dimensional (3D) structures, such as the knee, wrist or hind- and midfoot. In all patients with osteosynthesis material, hardware-induced artefacts still hamper computed tomography (CT) and magnetic resonance imaging (MRI), despite increasingly available high quality metal artefact reduction techniques. In patients after total knee arthroplasty, planar bone scintigraphy is known to have very high sensitivity for detecting loosening but lacks specificity and therefore falsepositive results limit definite diagnosis of loosening. Nuclear medicine uses radiopharmaceuticals for imaging as well as for radionuclide therapy and has a historically strong affinity with imaging of bone pathophysiology, first described in 1971 by Subramanian, et al. . Bone scintigraphy is performed with diphosphonates (Technetium-99m-hydroxydiphosphonate abbreviated as [99mTc] Tc-HDP and Technetium-99m-methylene diphosphonate, [99mTc]Tc-MDP). As an improvement over planar scintigraphy, Single Photon Emission Tomography (SPECT), enables 3D cross-sectional visualization of the distribution of the radiopharmaceutical. 1
14 Chapter 1 Subsequently, simultaneously acquired CT increases the accuracy (both sensitivity and specificity) by a combination of improved attenuation correction, enhanced localization of the radiopharmaceutical and in longer-existing pathology, the CT may reveal pathological structural changes. Similarly, Positron Emission Tomography (PET) also benefits from integrated CT (PET/CT). With improved accuracy of SPECT/CT and PET/CT over previous techniques, clinical impact has substantially increased since the early 2000s and therefore, both have experienced substantial growth in requests by clinicians and especially PET/CT has gainedmore central positions within clinical guidelines ever since. The clinical role of SPECT/CT after total knee arthroplasty is still under debate and evidence is currently scarce. As the existing evidence remains limited, this thesis does not pretend to offer a definite evidence-based imaging solution for all patients with a painful knee arthroplasty. Instead, it aspires to offer a step towards more standardized imaging for optimal results by clarifying the current evidence and limitations. Currently, inmost hospitals the imaging strategy in patients with a painful postoperative knee is often based on local preferences and individual experience of the treating physician. An evidence-based, protocolled and patient-tailored imaging strategy for advanced imaging after plain radiographs in patients with unexplained pain after knee arthroplasty would be the ultimate goal for the future to further improve patient’s quality of life after knee arthroplasty. A wide range of operative wrist and hand interventions are performed in congenital, traumatic, degenerative, or inflammatory diseases. For patients with post-operative hand and wrist pain, structured scientific literature is in general evenmore limited and is nearly nonexistent in the post-operative situation. This patient category would also benefit from an evidence-based imaging strategy to replace local choices defining various treatment and clinical outcome. Several imaging modalities are being used to evaluate the reason for painful postoperative wrists, such as standard conventional plain radiographs, ultrasound, CT, MRI, or bone scintigraphy. Conventional plain radiographs are a first-line imaging modality in patients with pain after surgery of the hand or wrist and may establish a diagnosis, such as nonunion or malposition. In patients with soft tissue disorders, ultrasound can conclusively evaluate tendon abnormalities, ganglion cysts, or superficial tumors. MRI delivers second-line imaging inmore complex soft tissue abnormalities. Standalone-CT visualizes the integrity and position of bones and metallic implants by avoiding superposition and adding crosssectional visualization. Still, patients may experience pain which is unexplained by the aforementioned modalities. The possible additional value of bone scintigraphy including SPECT/CT in these patients is explored and reviewed in this thesis.
15 General introduction and outline of this thesis In patients with tarsal coalitions, metabolic changes in bone metabolism and consequently subtle structural abnormalities of relatively small and anatomically challenging structures may define treatment and outcome. Therefore, the optimal modality should sensitively detect changed bone metabolism and precisely depict anatomical bone changes to inform the orthopedic surgeon on active local disease. In the follow-up of post-operative tarsal coalitions, especially talocalcaneal coalitions, plain radiographs lack sensitivity to discern active pathology. Current scientific literature on optimal use and limitations of bone-SPECT/CT in patients with tarsal coalitions is scarce, especially in the post-operative setting. This thesis analyses a small structured series of patients with tarsal coalition under consideration for surgery and in follow-up after surgery, and subsequently describes scenarios for the use of bone-SPECT/CT following plain radiographs. These scenarios aim to provide an evidence-based imaging strategy in patients with tarsal coalition and insufficiently explained symptoms. FD/MAS, current challenges for patients and their physicians FD/MAS is a rare benign disease caused by a somatic post-zygotic mutation in the G-nucleotide binding protein alpha sub unit (GNAS1) on chromosome 20q13.32 and usually presents around adolescence, with a wide age range [10, 11]. In this metabolic bone disease, normal bone is being replaced by fibrous tissue, which has a structure and quality inferior to healthy bone. Clinical presentation varies from an accidental finding of a solitary small extra-articular lesion with limited to no complaints, to extensive bone disease causing considerable impairment and/or fractures. Any bone may be affected: in monostotic fibrous dysplasia, one single bone is affected, comprising the majority of FD/MAS-patients. In the polyostotic form, multiple bones are affected, as shown in Figure 1, panel A. If FD is accompanied with hyperpigmented skin lesions (café-au-lait macules), and endocrinopathies such as precocious puberty, it is calledMcCune-Albright syndrome. Typical skin presentation is shown in Figure 1, panel B. In severe FD/MAS, the personal impact can be enormous. Not only may it instigate physical problems such as deformity, fractures, pain and hamperedmobility, but also due to psychological effects, such as stigma, depression, and anxiety . 1
16 Chapter 1 Figure 1, panel A: Severe bone deformation of the left leg and left iliac bone by FD in a 43-yearold female patient with polyostotic fibrous dysplasia from our study  using 3D rendering from low-dose CT. Figure 1, panel B: A 5-year-old girl, with hyperpigmented skin lesions (café au lait macules) with McCune-Albright syndrome. Source: Adapted fromCollins MT, Singer FR, Eugster E. McCune-Albright syndrome and the extraskeletal manifestations of fibrous dysplasia. Orphanet J Rare Dis. 2012 May 24;7 Suppl 1(Suppl 1):S4. doi: 10.1186/1750-1172-7-S1-S4 (Open Access, Creative Commons Attribution License). To date, there is no cure for FD/MAS. However, treatment with denosumab, altering bone remodeling by targeting Receptor Activator of Nuclear Factor-κB ligand (RANKL), has recently shown promising results in the management of selected FD patient groups, for both pain reduction and prevention of pathological fractures . Increased bone formation, such as caused by FD/MAS, can be biochemically reflected by an increase in serum alkaline phosphatase (ALP) and procollagen type 1 N-terminal propeptide (P1NP) in serum analysis, whereas the observed increased
17 General introduction and outline of this thesis bone resorption is reflected by an increase in serum telopeptides of type 1 collagen (CTX). Fibroblast growth factor 23 (FGF-23) is also used as a biomarker for disease activity as this is produced by FD lesions causing renal phosphate wasting . These serum bone turnover markers (BTMs) are used in assessment of FD-burden at diagnosis and follow-up, as they readily available and inexpensive, but above all able to reflect clinically relevant systemic bone changes. However, these serum measurements are incapable of characterizing the disease on a lesional level, thus not always reflecting clinical burden. An ideal instrument could impact clinical decisions by pinpointing location (intra-, juxta-, or extra-articular, craniofacial, or a less hampering site), and different characteristics of FD-lesions causing individually heterogeneous burden and response to treatment. Secondly, clinicians might encounter FD/MAS-patients with normal(ized) serum BTMs and remaining or recurrent complaints, needing an objective alternative measurement of FD-burden or complication. Planar bone scintigraphy with semiquantitative per-segment estimation, called Skeletal Burden Score (SBS), is only partially able to meet demands for estimating skeletal FD-burden, as discussed below in more detail. Therefore, these specialists desire a new reliable technique to assess usefulness and efficacy of novel therapy (denosumab) during follow-up. Lastly, although medical intervention may slow down the pace of bone deformation, the acquired deformations are still irreversible with medication alone. When deformations lead to facial distortion, reconstructive surgery may be needed, and, in severely weakened bone, orthopaedic surgery may be required to prevent or repair (threatening) fractures. The surgical aspects in FD/MAS are beyond the scope of this thesis, however. Current imaging of FD/MAS and its limitations Different radiological imaging techniques show varying accuracy for detection of different benign bone and joint diseases. Widely available, plain radiographs (X-rays) are often used as first-line imaging at relatively low cost and radiation exposure, with sensitivity being locally adequate in suspected fibrous dysplasia (FD/MAS) in especially the extremities. In complex 3D-bone structures, however, such as the spine or facial bones, plain radiographs have limited sensitivity and they are also less suitable for total skeletal imaging. Of the advanced radiological techniques, CT performs well in reflecting the anatomy of bony structures but lacks sensitivity for early detection of pathophysiological changes of the bone and for differentiating active and nonactive disease. On CT, large enough anatomical changes (sclerosis) 1
18 Chapter 1 as a result of the aforementioned osteoblast activity will only show after months of increased turnover. MRI has in general high sensitivity with especially precise imaging of soft tissues, but relatively low specificity for bone lesions and the imaging of the bony structures can be limited, especially in regions of avid bone marrow edema. Also, MRI is nearly always utilized to image limited parts of the body because of relatively long acquisition times with restricted field of view, which may be restricting in certain multifocal diseases, such as polyostotic FD/MAS. In order to assess the skeletal burden of FD/MAS, planar bone scintigraphy is currently frequently used. This modality is useful in clinical practice as an adjunct to determine the skeletal burden of FD/MAS, with the semiquantitative per-segment estimation using planar bone scintigraphy called Skeletal Burden Score (SBS), first postulated by Collins, et al. in 2005  and without methodological changes thereafter. Although PET using sodium fluoride-18 (Na[18F]F-PET) was already introduced in 1962 by Blau, et al.  and approved by the FDA in 1972, its use is still limited because of (perceived) costs and availability of both the radiopharmaceutical and PET/CT-scanner capacity. Modern molecular imaging solutions in bone disease In the past decade, Na[18F]F-PET/CT is gaining popularity over bone scintigraphy because of improved recovery by modern PET/CT-scanners, better availability and reduced costs of the radiopharmaceutical and PET/CT-scanners, and thus meeting a growing demand for improved diagnostic accuracy. Na[18F]F-PET/CT images bone (patho-)physiology, mainly osteoblast activity. On a molecular physiological level, osteoblasts and osteoclasts perform their functional tasks of bone formation and resorption continuously and harmonically within all bones in healthy people. Bone pathology generally leads to a disbalance between the level of activity of osteoblasts and osteoclasts. From this perspective, bone disease can therefore be classified into osteoclastic, osteoblastic or combined phenotype. In most benign bone and joint diseases, the osteoblastic component is largely dominant. Bone scintigraphy including bone-SPECT/CT and Na[18F]F-PET/CT both sensitively image in vivo osteoblast activity by injection of a radiopharmaceutical. The uptake mechanism reflecting the young osteoblasts of both radiopharmaceuticals is slightly different, but both are influenced by regional bone perfusion and ultimately attach to the surface of hydroxyapatite crystals by chemisorption [18, 19]. Na[18F]F, being a much smaller compound, has favorable pharmacokinetics, with faster blood clearance and high first pass extraction, low non-specific protein binding, bone uptake via chemisorption .
19 General introduction and outline of this thesis Thus Na[18F]F-PET is able to detect changes in osteoblast activity swiftly after onset. The expression of Na[18F]F-uptake in human bone reflecting young osteoblasts is depicted in this schematic drawing (Figure 2): Figure 2. Na[18F]F and [99mTc]Tc-MDP-uptake in human bone by hydroxyapatite, reflecting young osteoblasts. After intravenous injection of Na[18F]F, the OH--ions in hydroxyapatite [Ca 10(PO4)6(OH)2] are exchanged for 18F--ions, converting hydroxyapatite to fluorapatite Source: adapted fromhttps://commons.wikimedia.org/wiki/File:Bone_regeneration_-_Bone_remodeling_cycle_I_-_Endosteal_Sinus_Monocyte_Pre-osteoclast_etc_--_Smart-Servier.jpg (Creative Commons Attribution-Share Alike 3.0 Unported license). Hydroxyapetite structure adapted from: Pecheva, Emilia & Pramatarova, Lilyana. (2006). Modified Inorganic Surfaces as a Model for Hydroxyapatite Growth. 1
20 Chapter 1 Bone scintigraphy with SBS has several technical limitations in comparison to Na[18F]F-PET/CT: 1. SBS is based on planar imaging, while the human skeleton is a three-dimensional (3D) structure, and especially the thorax, spine and pelvis and are frequently affected by FD/MAS. The skeletal burden cannot be precisely visualized using planar (2D) imaging. 3D cross-sectional imaging provides more precise information on the extent of involved skeletal structures and thus skeletal burden. Although SPECT-imaging could benefit from this improvement over planar scintigraphy, whole body SPECT/CT is seldomly performed, as the acquisition would be very time-consuming. 2. The spatial resolution of both planar bone scintigraphy and SPECT are inferior to PET (roughly 8mm vs just above 3 mm full-width at half maximum). 3. Patient preparation of Na[18F]F-PET/CT is more patient friendly than [99mTc]Tc-HDP SPECT/CT since the used PET-radiopharmaceutical has a shorter incubation time: 3 to 4 hours for [99mTc]Tc-HDP to around 45 to 60 minutes for Na[18F]F-PET/CT. Secondly, acquisition of [99mTc]Tc-HDP plus one table position SPECT/CT takes approximately 35 minutes, compared to 12 to 15 minutes for acquisition and potentially much faster with modern PET/CT-scanners . 4. SBS determination is semiquantitative, less precise, and is limited to a weighted sum of the per-segment estimation of the percentage of affected normal bone volume. The weighting factors used are based on average representation of that segment within the skeleton. Some FD-affected locations may cause disproportionate pain complaints, especially in expansile lesions. In these patients SBS might be an underestimation, for example in the ribs. Furthermore, the weighting factors of all skeletal segments as proposed by Collins, et al. sum up to 0.998, which remains unexplained . Thus,Na[18F]F-PET/CTshouldtheoreticallyhave important advantagesover [99mTc]Tc-HDP including SBS and over serum BTMs. As far as we know after careful research of the literature, no study on FD/MAS using (quantitative) Na[18F]F-PET/CT had been performed at the time of our study. This thesis investigates the conceptualization for use of quantitative Na[18F]F-PET/CT and its (possible) role to improve both primary assessment of skeletal FD-burden and quantifying treatment response after bone remodeling therapy (Part II). This part of the dissertation discusses challenges in quantifying normal bone in relation of Na[18F]F- uptake, including factors that might influence bone metabolism, patient variation and which methodologies to consider when determining normal bone reproducibly
21 General introduction and outline of this thesis and reliably on Na[18F]F-PET/CT. Secondly, measurements of pathological bone in FD/ MAS-patients and its relevance in clinical practice will be discussed. Two relevant unmet needs are selected regarding FD/MAS-patients: 1. the need for accurate and reproducible assessment of the FD/MAS-related skeletal burden in primary diagnosis, as other currently used clinical methods show limitations. 2. the need to assess change in FD/MAS-related skeletal burden accurately and reproducibly in follow-up after treatment, e.g., with the RANKL-inhibitor denosumab, in conjunction with clinically relevant measures (pain, quality of life and serum BTMs). This thesis aims to contribute to the evidence of strengths, weaknesses and suggested clinical use of bone-SPECT/CT and Na[18F]F-PET/CT for early detection of benign bone and joint diseases at initial diagnosis and with special interest in followup after surgery in orthopedic indications and after bone remodeling medication in FD/MAS. Quantification of skeletal burden in patients with FD/MAS using Na[18F]F-PET/CT Not all increased tracer uptake on Na[18F]F-PET/CT solely reflects bone disease, let alone FD/MAS. Firstly, extra-osseous uptake is normal in especially the kidneys and urinary bladder due to renal clearance of the radiopharmaceutical. Secondly, Na[18F]F-uptake is not specific to the disease under study, e.g., active growth plates in pediatric patients and osteoarthritis in adults and in elderly patients will demonstrate strongly increased bone turnover and of uptake intensity alone will not discriminate FD/MAS from osteoarthritis. Thirdly, osteoarthritis is particularly prevalent in patients with FD/MAS, not only due to age but also secondary to the deformative nature of FD/MAS. Moreover, osteoarthritis activity may progress over time. Therefore, uptake caused by osteoarthritis is expected to affect intra-patient measurements of skeletal FD-burden. Our studies should describe how to optimize wholebody measurements to include all FD uptake by manual exclusion of nonspecific uptake and extra-osseous uptake when measuring FD. This requires image interpretation combined with knowledge of the radiologic features of alternative diagnoses. Lastly, we will describe the improvements that could be possible in future measurement methodologies. For illustration of the method measuring FD and excluding other irrelevant sites of increased tracer uptake, Figure 3 exemplifies such a measurement. 1
22 Chapter 1 Figure 3. FD-burden measurement of a lesion in the left intertrochanteric region (depicted with ‘FD’ in blue). At the right side the volume of interest semi-automatically drawn including the FD lesion limited by cut-off-defined thresholds. A site of osteoarthritis at the lumbosacral junction (depicted with ‘OA’ in red) and physiological uptake in kidneys and urinary bladder were deliberately not measured. Outline of this thesis This thesis investigates the role of two specific advanced multimodality molecular imaging techniques, bone-SPECT/CT and Na[18F]F-PET/CT, in selected benign bone and joint disease before and after treatment. In Part I of this thesis, the EANM guideline on bone scintigraphy (Chapter 2) summarizes the role of bone scintigraphy using [99mTc]Tc-oxidronate including Single Photon Emission Computed Tomography / Computed Tomography (bone-SPECT/CT) in (suspected) bone disease. Chapter 3 describes optimal advanced imaging using bone-SPECT/CT in patients with a post-operative painful knee. Chapter 4 portrays the evidence for use of bone-SPECT/CT in patients with painful post-operative hand and
23 General introduction and outline of this thesis wrist, in order to answer the research question what the current scientific evidence for bone-SPECT/CT is in these patients, as well as usefulness for clinical application. To assess the value of bone-SPECT/CT in patients with a tarsal coalition with insufficiently explainedpain Chapter 5 was designed to elucidatewhenbone-SPECT/CT is beneficial in patients with tarsal coalitions at primary diagnosis and in follow-up after surgery, by critically illustrating features and by discussing in-depth indications, limitations, relations to other imaging techniques and impact of bone-SPECT/CT on patient care, and by providing a suggested imaging workflow for these patients. Part II of this thesis aims to address the clinically unmet need for accurately localizing FD/MAS-related skeletal burden at primary diagnosis and during follow-up after treatment with denosumab. An observational cohort of FD/MAS-patients that underwent Na[18F]F-PET/CT will be retrospectively analyzed. Chapter 6 primarily answers the research question whether Na[18F]F-uptake using PET/CT at primary diagnosis of FD/MAS could adequately quantify healthy bone metabolism and localized FD skeletal burden in relation to clinical and biochemical parameters used for FD/MAS. Secondary aims consist of comparing normalization for volume of distribution, and determining reproducibility of Na[18F]F-PET/CT uptake parameters in healthy bone and in FD/MAS, and to relate quantified Na[18F]F-uptake to the current imaging standard, the skeletal burden score using bone scintigraphy, to bisphosphonate therapy and pain. Chapter 7 contains our scientific response to a suggested procedure by other authors, hypothesizing possible improvement on our quantification methodology, by correcting for skeletal volume on the corresponding low-dose non-contrast enhanced CT of the Na[18F]F-PET/CT. Chapter 8 describes our analyses on (quantitative) Na[18F]F-PET/CT during follow-up, and the ability of Na[18F]F-PET/CT in capturing treatment-induced skeletal changes and whether this correlated with the clinically relevant serum BTMs and pain reduction. In Chapter 9, two cases of patients with FD/MAS and the response on both plain radiographs and Na[18F]F-PET/CT after treatment with denosumab are presented. Thus, this thesis aims to contribute to scientific evidence in optimizing patienttailored diagnosis for the abovementioned benign bone and joint diseases and aspires to encourage follow-up research in the future. Last, but not least, it hopes to serve as a practical guide in daily practice for medical specialists with interest in the subject of advanced imaging in benign bone and joint disease. 1
24 Chapter 1 References 1. Hay S, Jayaraman S, Truelsen T, Sorensen R, Millear A, Giussani G, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388(10053):1545-602. 2. Lewis R, Gómez Álvarez CB, Rayman M, Lanham-New S, Woolf A, Mobasheri A. Strategies for optimising musculoskeletal health in the 21(st) century. BMC Musculoskelet Disord. 2019;20(1):164. 3. Allen C, Biryukov S, Giussani G, Gugnani H. Global, regional, and national disability-adjusted life-years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE), 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388(10053):1603-58. 4. RIVM in opdracht van het Ministerie van Volksgezondheid WeSVMvV, Welzijn en Sport. CBS Gezondheidsenquete 2020; https://vzinfo.nl/artrose/leeftijd-en-geslacht. 5. RIVM in opdracht van het Ministerie van VolksgezondheidWeSVMvV, Welzijn en Sport. https://www.vzinfo.nl/artrose/zorguitgaven. 2022. 6. Hunter DJ, Schofield D, Callander E. The individual and socioeconomic impact of osteoarthritis. Nat Rev Rheumatol. 2014;10(7):437-41. 7. Rice DA, Kluger MT, McNair PJ, Lewis GN, Somogyi AA, Borotkanics R, et al. Persistent postoperative pain after total knee arthroplasty: a prospective cohort study of potential risk factors. Br J Anaesth. 2018;121(4):804-12. 8. van der List JP, Sheng DL, Kleeblad LJ, Chawla H, Pearle AD. Outcomes of cementless unicompartmental and total knee arthroplasty: A systematic review. Knee. 2017;24(3):497-507. 9. Subramanian G, McAfee JG. A new complex of 99mTc for skeletal imaging. Radiology. 1971;99(1):192-6. 10. Javaid MK, Boyce A, Appelman-Dijkstra N, Ong J, Defabianis P, Offiah A, et al. Best practice management guidelines for fibrous dysplasia/McCune-Albright syndrome: a consensus statement from the FD/MAS international consortium. Orphanet J Rare Dis. 2019;14(1):139. 11. Chapurlat RD, Gensburger D, Jimenez-Andrade JM, Ghilardi JR, Kelly M, Mantyh P. Pathophysiology and medical treatment of pain in fibrous dysplasia of bone. Orphanet J Rare Dis. 2012;7 Suppl 1:S3. 12. van der Bruggen W, Hagelstein-Rotman M, de Geus-Oei LF, Smit F, Dijkstra PDS, Appelman-Dijkstra NM, et al. Quantifying skeletal burden in fibrous dysplasia using sodium fluoride PET/CT. Eur J Nucl Med Mol Imaging. 2020;47(6):1527-37. 13. Konradi A. Fibrous dysplasia patients with and without craniofacial involvement report reduced quality of life inclusive of stigma, depression, and anxiety. Chronic Illn. 2021:17423953211049436. 14. Majoor BCJ, Papapoulos SE, Dijkstra PDS, Fiocco M, Hamdy NAT, Appelman-Dijkstra NM. Denosumab in Patients With Fibrous Dysplasia Previously Treated With Bisphosphonates. J Clin Endocrinol Metab. 2019;104(12):6069-78. 15. Majoor BC, Appelman-Dijkstra NM, Fiocco M, van de Sande MA, Dijkstra PS, Hamdy NA. Outcome of Long-TermBisphosphonate Therapy in McCune-Albright Syndrome and Polyostotic Fibrous Dysplasia. J Bone Miner Res. 2017;32(2):264-76. 16. Collins MT, Kushner H, Reynolds JC, Chebli C, Kelly MH, Gupta A, et al. An instrument to measure skeletal burden and predict functional outcome in fibrous dysplasia of bone. J Bone Miner Res. 2005;20(2):219-26. 17. Blau M, Nagler W, Bender MA. Fluorine-18: a new isotope for bone scanning. J Nucl Med. 1962;3:332-4.
25 General introduction and outline of this thesis 18. Ahuja K, Sotoudeh H, Galgano SJ, Singh R, Gupta N, Gaddamanugu S, et al. (18)F-Sodium Fluoride PET: History, Technical Feasibility, Mechanism of Action, Normal Biodistribution, and Diagnostic Performance in Bone Metastasis Detection Compared with Other Imaging Modalities. J Nucl Med Technol. 2020;48(1):9-16. 19. Park PSU, Raynor WY, Sun Y, Werner TJ, Rajapakse CS, Alavi A. (18)F-Sodium Fluoride PET as a Diagnostic Modality for Metabolic, Autoimmune, and Osteogenic Bone Disorders: Cellular Mechanisms and Clinical Applications. Int J Mol Sci. 2021;22(12). 20. Lasnon C, Coudrais N, Houdu B, Nganoa C, Salomon T, Enilorac B, et al. How fast can we scan patients with modern (digital) PET/CT systems? Eur J Radiol. 2020;129:109144. 1
PART I OVERVIEWOF MOLECULAR IMAGING IN BONE DISEASES & BONE-SPECT/CT OF THE EXTREMITIES
We’ve all got stardust in our bones - Ben Harper
CHAPTER 2 The EANM practice guideline for Bone Scintigraphy Eur J Nucl Med Mol Imaging. 2016 Aug;43(9):1723-38 Van den Wyngaert T1, Strobel K2, Kampen WU3, Kuwert T4, van der Bruggen W5, Mohan HK6, Gnanasegaran G7, Delgado-Bolton R8, Weber WA9, Beheshti M10, Langsteger W10, Giammarile F11, Mottaghy FM12, and Paycha F13. On behalf of the EANM Bone & Joint Committee and the Oncology Committee. Affiliations: 1Dept. of Nuclear Medicine, Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium Faculty of Medicine andHealth Sciences, University of Antwerp, Universiteitsplein 1, 2610Wilrijk, Belgium 2Dept. of Radiology and Nuclear Medicine, Lucerne Cantonal Hospital, Lucerne, Switzerland 3 Dept. of Nuclear Medicine Spitalerhof, Spitalerstraße 8, 20095 Hamburg, Germany 4Clinic of Nuclear Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany 5Radiology and Nuclear Medicine, Slingeland Hospital, Doetinchem, The Netherlands 6Dept. of Nuclear Medicine, Guy’s and St Thomas’ NHS Foundation Trust, London, UK 7Dept. of Nuclear Medicine, Royal Free London NHS Foundation Trust, London, United Kingdom 8Dept. of Diagnostic Imaging (Radiology) and Nuclear Medicine, San Pedro Hospital and Centre for Biomedical Research of La Rioja (CIBIR), University of La Rioja, Logroño, La Rioja, Spain 9Dept. of Radiology, Memorial Sloan Kettering Center, New York, NY, USA 10PET - CT Center LINZ, Dept. of Nuclear Medicine & Endocrinology, St Vincent’s Hospital, Seilerstaette 4, A-4020 Linz, Austria 11Dept. of Nuclear Medicine, Centre Hospitalier Universitaire de Lyon, Lyon, France 12Dept. of Nuclear Medicine, University Hospital Aachen, RWTH Aachen University, Aachen, Germany and Nuclear Medicine, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands 13Dept. of Nuclear Medicine, Hôpital Lariboisière, 2 rue Ambroise Paré, 75010 Paris, France 6Biomedical Photonic Imaging Group, University of Twente, Enschede, the Netherlands
30 Part I Chapter 2 Abstract Purpose The radionuclide bone scan is the cornerstone of skeletal nuclear medicine imaging. Bone scintigraphy is a highly sensitive diagnostic nuclear medicine imaging technique that uses a radiotracer to evaluate the distribution of active bone formation in the skeleton related to malignant and benign disease, as well as physiologic processes. Methods The European Association of Nuclear Medicine (EANM) has written and approved these guidelines to promote the use of nuclear medicine procedures with high quality. Conclusion The present guideline offers assistance to nuclear medicine practitioners in optimizing the diagnostic procedure and interpreting bone scintigraphy. This guideline describes the protocols that are currently accepted and used routinely, but does not include all existing procedures. They should therefore not be taken as exclusive of other nuclear medicinemodalities that can be used to obtain comparable results. It is important to remember that the resources and facilities available for patient care may vary.
31 The EANM practice guideline for Bone Scintigraphy Preamble The aim of this document is to provide general information about bone scintigraphy. This guideline describes current routine clinical procedures but should not be interpreted as excluding alternative procedures also employed to obtain equivalent data. It is important to remember that the resources and facilities available for patient care may vary from one country to another and from one medical institution to another. This document has been prepared primarily for nuclear medicine physicians, physicists and technicians and intends to offer assistance in optimising the procedural protocols and diagnostic information that can currently be obtained from bone scintigraphy. The guideline has been written by the EANM Bone & Joint and Oncology Committees and then reviewed and approved by all EANM Committees and the Board, as well as by the National Societies represented within the EANM. The European Association of Nuclear Medicine (EANM) has written and approved guidelines to promote the use of high-quality nuclear medicine procedures. These guidelines are intended to assist practitioners in providing appropriate nuclearmedicine care for patients. They are not inflexible rules or requirements of practice and are not intended, nor should they be used, to establish a legal standard of care. For these reasons and those set forth below, the EANM caution against the use of these guidelines in litigation in which the clinical decisions of a practitioner are called into question. The ultimate judgment regarding the propriety of any specific procedure or course of action must be made by medical professionals taking into account the unique circumstances of each case. Thus, an approach that differs from the guidelines does not necessarily imply that the approach was below the standard of care. To the contrary, a conscientious practitioner may responsibly adopt a course of action different from that set forth in the guidelines when, in the reasonable judgment of the practitioner, such course of action is indicated by the condition of the patient, limitations of available resources, or advances in knowledge or technology subsequent to publication of the guidelines. The practice ofmedicine involves not only the science, but also the art of dealingwith the prevention, diagnosis, alleviation, and treatment of disease. The variety and complexity of human conditionsmake it impossible at times to identify themost appropriate diagnosis or to predict with certainty a particular response to treatment. Therefore, it should be recognized that adherence to these guidelines will not assure an accurate diagnosis or a successful outcome. All that should be expected is that the practitioner will follow a reasonable course of action based on current knowledge, available resources, and the needs of the patient to deliver effective and safemedical care. The sole purpose of these guidelines is to assist practitioners in achieving this objective. 2
32 Part I Chapter 2 Introduction and goals The radionuclide bone scan is the cornerstone of skeletal nuclear medicine imaging. Bone scintigraphy is a highly sensitive diagnostic nuclear medicine imaging technique that uses a radiotracer to evaluate the distribution of active bone formation in the skeleton related to malignant and benign diseases, as well as physiologic processes. Phosphate analogues can be labelled with technetium-99m (99mTc) and are used for bone imaging because of their high uptake in the skeleton and rapid clearance from soft tissues after intravenous injection. Tracer accumulation occurs in proportion to local blood flow and bone remodeling activity (dependent on osteoblast-osteoclast activity), and unbound tracer is rapidly cleared from surrounding soft tissues. Most pathologic bone conditions, whether of infectious, traumatic, neoplastic or other origins, are associated with an increase in vascularization and local bone remodeling. This accompanying bone reaction is reflected on bone scan as a focus of increased radioactive tracer uptake. Bone scintigraphy is a sensitive technique that can detect significant metabolic changes very early, often appearing several weeks or even months before they become apparent on conventional radiological images. In addition, the technique provides an overview of the entire skeleton at a relatively modest radiation exposure. While MRI has been shown to be more sensitive than planar bone scans in detecting skeletal metastases in vertebral bodies, a comparable diagnostic sensitivity was found with bone SPECT for vertebral body metastases and a higher diagnostic sensitivity for metastases localized in the pedicles . Furthermore, the majority of studies that compared bone scanning with MRI did not use a reliable gold standard and typically included various solid tumors and even lymphomas which usually produce osteolytic lesions with poor osteoblastic bone reaction so that they are not detectable by bone scintigraphy. Hence, there is no reliable evidence that bone scintigraphy is generally less sensitive than whole-body MRI in all solid cancers. Multimodality SPECT/CT offers the unique opportunity to correlate the scintigraphic findings with anatomical images and introduces novel algorithms to further enhance SPECT image quality based on CT data (e.g. correction for attenuation and scatter). This results in improved correlation of areas with physiological variants or abnormal tracer accumulation to anatomical landmarks . However, this has increased the complexity of this technique, increasing the need for standardization and practice guidelines in order to maximize the diagnostic yield of the exam.
33 The EANM practice guideline for Bone Scintigraphy The corresponding guidelines from the Society of Nuclear Medicine and Molecular Imaging (SNMMI), the Dutch Society of Nuclear Medicine (NVNG), and the French Society of Nuclear Medicine and Molecular Imaging (SFMN), as well as the existing EANM bone scintigraphy procedures guideline for tumor imaging have been consulted while preparing this consensus document [3-6]. For specific applications of bone scintigraphy in selected indications or populations, the reader is also referred to the EANM guidelines for paediatric bone scanning, and the EANM and SNMMI practice guidelines for sodium 18F-Fluoride PET/CT bone scans [7-9]. Other excellent reference works are recommended as well . The goal of this guideline is to offer an educational tool designed to assist the nuclear medicine practitioner in appropriately recommending, performing, interpreting, and reporting the results of bone scintigraphy. Definitions 1. Planar whole body images in anterior and posterior projections of the axial and appendicular skeleton. If necessary, additional localized or spot views can be obtained. 2. Focal planar images limited to a specific portion of the skeleton. 3. Single photon emission tomography (SPECT, also known as SPET) allows the visualization of the three-dimensional distribution of the radiopharmaceutical in the skeleton. 4. SPECT/CT images consist of a SPECT acquisition combined with a Computed Tomography (CT) using an integrated CT scanner. 5. Multi-phase bone scan produces planar images of the vascular inflow, the soft tissue phase, and delayed phase images of the radiopharmaceutical over a given area of the skeleton. The vascular inflow images are acquired during intravenous injection. The study of the soft tissue distribution of the radiopharmaceutical in the region of interest is performed within the first 5 - 10 minutes after injection. Finally, delayed whole body, focal views, and/or tomographic images are usually acquired between two and four hours after injection of the radiopharmaceutical. In some cases, it may be useful to acquire late-phase images, up to until 24 hours after tracer administration . 6. Quantification is the process of calculating the osseous radioactivity concentration expressed as standardized uptake values (SUV). 2
34 Part I Chapter 2 Common clinical indications for bone scan The indications for bone scintigraphy are numerous and can generally be classified into three distinct clinical scenarios: a) when a specific bone disease is present or suspected, b) to explore unexplained symptoms, or c) for the metabolic assessment prior to the start of therapy. While the diagnostic sensitivity of bone scintigraphy is very high, the low specificity often requires further investigation with other imaging modalities (like X-ray, CT or MRI) or nuclear medicine studies (e.g. FDG-PET/CT). For this reason, anatomical imaging and bone scintigraphy should be considered as complementary methods, which cannot be replaced by each other. Conversely, bone scintigraphy is not indicated in a number of specific conditions, due to limitations of the technique in a specific disease context or lack of clinical impact of imaging results. However, ultimately it must be the Nuclear Medicine physician who evaluates and decides on the indication of each particular case and on the specific protocol that should be applied. Both indications and non-recommended indications are outlined below: Bone scan is indicated in case bone disease is present or suspected 1. Oncology • Solid tumours with high affinity for bone, including prostate-, breast-, lung-, renal cancer [12-17]. • Malignant hematological conditions limited to bone, including Hodgkin’s disease, non-Hodgkin lymphoma . • Bone tumours and bone dysplasia, including osteosarcoma, osteoid osteoma, osteoblastoma, fibrous dysplasia, giant cell tumor, osteopoikilosis . • Soft tissue sarcomas, such as rhabdomyosarcoma. • Paraneoplastic syndromes, including hypertrophic pulmonary osteoarthropathy, algodystrophy, polymyalgia rheumatica, poly(dermato)myositis, and osteomalacia. • Assessment of bone remodeling prior to radionuclide therapy (223Ra, 89Sr, 153Sm-EDTMP, 186Re-HEDP). Whole-body FDG-PET or PET/CT are other imaging modalities that enable detection of the primary tumour and metastases by visualisation of the increased glucose consumption of malignant tissue. The majority of studies comparing FDG-PET with 18F-Fluoride PET or SPECT with Technetium-99m labelled bisphosphonates reported a higher diagnostic sensitivity of FDG for osteolytic metastases and a higher diagnostic sensitivity of bone-affine radiotracers for detecting osteoblastic metastases [20-24].
35 The EANM practice guideline for Bone Scintigraphy Primary tumours of bone are relatively rare in adults whereas bone metastases of other cancer entities (e.g. breast, prostate, lung, renal cancer, etc.) are very frequent. In prostate cancer, the assessment of bone scans is increasingly standardized by calculation of the bone scan index and reporting of progression according to PCWG-2 criteria [25, 26]. 2. Rheumatology • Chronic inflammatory arthritis, including rheumatoid arthritis, spondyloarthropathies and related disorders (ankylosing spondylitis, psoriatic arthritis, Reiter’s arthritis, SAPHO syndrome [synovitis, acne, pustulosis, hyperostosis, osteitis], chronic recurrent multifocal osteomyelitis), and sacroiliitis [27-29]. • Osteoarthritis of the lumbar facet joints, hip, femoro-tibial and femoro-patellar osteoarthritis, rhizarthrosis, and tarsal osteoarthritis [30, 31]. • Enthesopathies, such as plantar fasciitis, Achilles tendinitis or bursitis. • (Avascular) osteonecrosis, which is most frequently located at the femoral head, femoral condyle, and tibial plateau. • Osteonecrosis of the jaw (ONJ)  • Complex regional pain syndrome type I of the hand, hip, knee, and foot. • Tietze’s syndrome (costochondritis) • Polymyositis • Paget’s disease • Langerhans cell histiocytosis (LCH): Single system LCH and multi-system LCH with bone involvement. • Non-Langerhans cell diseases, such as Erdheim–Chester disease, Schnitzler syndrome, and Rosaï Dorfman disease. • Other rare osteo-articular diseases, such as sarcoidosis with bone involvement, mastocytosis, Behçet’s disease, and familial Mediterranean fever. 3. Bone and joint infections  • Osteomyelitis acute, subacute, or chronic of bacterial, mycobacterial or fungal origin • Septic arthritis • Spondylodiscitis or spondylitis • Septic loosening or mechanical complication of internal fixation (long bones or spine) or arthroplasty (hip, knee, ankle, or shoulder) • Malignant (necrotising) external otitis The reader is also referred to other relevant EANM consensus documents and guidelines [34, 35]. 2www.proefschriften.net