The Use of Neo – Adjuvant Denosumab in Treatment of Giant Cell Tumours of the Spine

The Use of Neo – Adjuvant Denosumab in Treatment of Giant Cell Tumours of the Spine | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Use of Neo – Adjuvant Denosumab in Treatment of Giant Cell Tumours of the Spine Nicolas Beresford-Cleary, Charlotte Dandurand, Gerard Mawhinney, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2405951/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background The current recommended treatment for Giant Cell Tumour of the spine is en bloc excision. Denosumab is a monoclonal RANKL inhibitor that shows promising results when used as a neo – adjuvant treatment. The purpose of this study was to assess the effect of Denosumab on tumour characteristics and symptom relief. Methods We performed a retrospective review of 12 patients treated with denosumab as neo adjuvant and stand - alone treatment. Tumour volume and PET SUV capitation measurements were taken before and after treatment and patients were interviewed for subjective pain responses. Clinical response was determined by reduction in tumour volume, PET SUV capitation, the Boriani calcification response classification, improvement in the Bilsky epidural grading and WBB layers and improvement in pain. Results Following treatment 75% of patients were pain free with 58% noting improvement within 48 hours. Mean relative volumetric reduction in tumour volume was 42%. All pathology specimens confirmed elimination of giant cells. Improvement in Bilsky epidural disease grading occurred in 7/12 cases. Median baseline SUVmax was 14.7 and post treatment was 3.3. Sixty - seven percent of patients demonstrated intralesional bone formation following treatment. At one year follow-up, there were no cases of local disease recurrence, malignant transformation or metastases. Conclusions This study demonstrates neo-adjuvant denosumab can facilitate en bloc resection by reducing the tumour burden around critical adjacent neurovascular structures, reducing the risk morbidity and improving preoperative pain. We recommend routine use when W-B-B – based criteria are fulfilled for en – bloc excision. Giant cell tumour denosumab neo – adjuvant en bloc excision pain Figures Figure 1 Figure 2 Background Giant cell tumours (GCTs) are osteolytic lesions that occur most frequently in the long bones. In the axial spine they most commonly involve the sacrum, and in the mobile spine the vertebral bodies, but can also involve the posterior elements, discs and paraspinal soft tissue [ 1 ]. They are locally aggressive and can be large at presentation. Typical presentation is with pain which often precedes diagnosis. Up to 72% of patients also experience neurological symptoms such as radiculopathy or symptoms of cord or cauda equina compression [ 2 ]. They commonly occur in patients aged 20–40 years, with a female – to – male ratio of 1.2:1 [ 3 ]. Despite being classified as a benign lesion, GCT can show malignant behaviour. Typical metastasis is via haematogenous spread to the lungs and occurs in 2–3% of cases. A small number may undergo sarcomatous change, most often to osteosarcoma, which can occur as a primary malignant GCT or more commonly as secondary malignancy after radiotherapy [ 2 ]. Treatment options include therapeutic embolisation, radiotherapy alone, intralesional surgery +/- radiotherapy and en bloc resection. Of these, en bloc resection is considered the Enneking appropriate treatment [ 4 ][ 5 ][ 6 ]. Surgical resection margins remain the best predictors of recurrence, and though intralesional resection may spare neural, bony and visceral structures, it does so at the cost of an increased risk of local recurrence, with rates up to 46% reported [ 7 ]. Radiotherapy alone and therapeutic embolization are associated with unacceptably high local recurrence rates [ 7 ][ 8 ]. En bloc resection gives the lowest chance of local recurrence and improves survival, but risks increased inter – operative and functional morbidity and may be unachievable due to anatomical constraints [ 4 ][ 5 ]. With the goal of facilitating en bloc resection, interest has grown in the role of denosumab in the neo – adjuvant setting. Denosumab is a human monocloncal antibody that reduces osteoclast activity by binding receptor of activator nuclear factor kappa – B ligand (RANKL). It has previously been shown to be effective in suppressing bone destruction in patients with multiple myeloma and bony metastases in solid tumours such as breast and prostate [ 9 ]. In 2010 Thomas et al conducted an open label phase 2 study investigating the effect of Denosumab on tumour cell survival and growth on 37 patients with recurrent or unresectable GCT. Eighty – six percent of patients had a tumour response defined as either elimination of at least 90% of giant cells, or no radiological progression of the target lesion up to week 25 [ 10 ]. A subsequent study of the histologic analyses of the samples taken, Branstetter et al concluded that in addition to significantly reducing or eliminating RANK positive tumour giant cells, Denosumab also reduced the content of tumour stromal cells and replaced them with nonproliferative, differentiated, densely woven new bone [ 9 ]. Multiple studies to date have demonstrated its efficacy in controlling surgically unresectable GCTs, and approval for its use was granted by the FDA in 2013 [ 2 ][ 11 ]. In 2015 Goldschlager et al reported on a series of 5 patients treated pre – operatively with Denosumab for GCT of the spine, and demonstrated a 100% radiological response to treatment, although one patient failed to demonstrate a histological response [ 12 ]. Despite these promising results, further evidence for the use of Denosumab in the neo – adjuvant setting is required. Intrusive pain is very common in these patients, and is observed to improve with Denosumab treatment, but there remains a paucity of evidence on this aspect of therapy. Nonetheless, the published literature that does exist is encouraging, with rates of improvement in pain of up to 80% reported when used in the neo – adjuvant setting [ 13 ]. Methods This study aimed to investigate the efficacy and safety of Denosumab when used in the neo – adjuvant setting in terms of improving tumour radiological characteristics for en bloc resection and symptom relief. We performed a retrospective study of prospectively collected data on 12 patients treated with neo – adjuvant Denosumab for GCT of the spine in a tertiary referral centre. The institutional review board approved the study. Patient population Inclusion criteria were: patients were 18 years or older at the time of treatment, had a primary diagnosis of biopsy – confirmed GCT of the mobile spine or sacrum, had received Denosumab as a primary or neo – adjuvant treatment, and had a minimum follow – up of 6 months after initiation of Denosumab treatment. Cases of recurrent GCT were excluded from the study. Data collection Patient demographic data was collected such as age, sex, and ethnicity. Clinical presentation was collected including pain severity and neurological status, duration of symptoms and previous treatment. Pain severity was graded as mild, moderate or severe. Details of the Denosumab treatment regimen were included, as well as duration of treatment. Patients were contacted directly, and a record was taken of the reported time taken for significant symptom improvement ( 6 weeks), patient – reported degree of symptom improvement (mild, moderate, large), and whether Denosumab effected complete resolution of symptoms. Surgical data was collected including type of surgical resection, surgical time and intraoperative blood loss. Final pathology reports were reviewed for final surgical margins and presence of tumoral cell giant cells and response to treatment. Intraoperative and postoperative adverse events (AEs) were collected. The details of the denosumab regimen were collected including duration, posology and denosumab related AEs. Outcomes were collected including tumour recurrence, progression, metastasis and malignant transformation. Tumour measurements based on imaging were collected at 3-month time intervals following Denosumab initiation and continued depending on duration of treatment. Volumetric analysis was performed based on these measurements. The Bilsky classification for epidural disease [ 14 ] as well as the Weinstein-Boriani-Biagini layers and sectors [ 15 ] and also Enneking staging [ 16 ] were recorded. The Boriani classification for Denosumab calcification response (Fig. 1 ) [ 6 ] was also noted. PET SUV capitation was measured to assess treatment response. Clinical response would be determined by volumetric reduction in tumour size, PET SUV capitation, the Boriani Classification and improvement in pain symptoms. Results (Tables follow references) 12 patients were included in the study, 5 males, 7 females (Table 1 ). Mean age was 38.1 years (11.8 years). Ten patients were Caucasian British, 1 Caucasian Romanian, 1 Pakistani British. Table 1 Clinical presentation, severity of pain, neurological status and symptoms duration. Patient Clinical presentation Pain severity at presentation Neurological status at presentation Symptom duration at presentation (months) A Back pain Moderate Intact 4 B Neck pain & b/l UL radicular pain Moderate Intact 2 C LBP Moderate Intact 4 D Thoracic & RUL radicular pain Mild Intact 8 E Left iliac crest pain Moderate Intact Data not available F LBP + b/l LL radicular pain Severe Intact 3 G LBP, left LL radicular pain, sphincter disturbance Severe Sphincter disturbance, unspecified Pain: 15 Sphincter disturbance: 3 H Left LL radiculopathy, perineal pain & dysaesthesias Severe Unable to walk; bladder/bowel incontinence at presentation Pain: 4 I Thoracic pain, bladder/bowel disturbance Severe Thoracic myelopathy, gait/bladder/bowel disturbance (non specific) Data not available J Thoracic pain Severe Data not available Data not available K Cervical pain Severe C6 ASIA D > 6 L Thoracic pain Severe Intact > 6 UL: Upper Limb LL: Lower Limb b/l: Bilateral Mean duration of pain at presentation was 5.8 months (3.9 months). This information was not available for 3 patients. Treatment regimen with Denosumab was uniform for all patients and comprised weekly administration on days 1, 8 and 15, and then monthly thereafter. Mean duration of treatment was 8.2 months (10 months). Nine out of 12 patients were pain free following treatment (Table 2 ). Seven out of 12 patients reported significant improvement in pain within 48 hours. Table 2 Symptom response Patient Pain severity at presentation Duration of tx (months) Time until significant symptom improvement Degree of symptom improvement Pain free post Denosumab treatment? A Moderate 6 > 6 weeks Moderate Yes B Moderate 5 6 weeks Moderate Yes C Moderate 5 6 weeks Mild Yes E Moderate 8 < 48 hrs Large No F Severe 7 6 weeks Moderate No H Severe 39 (20 + 19) < 48 hrs Large Yes I Severe 7 6 weeks Moderate No J Severe 2 < 48 hrs Large Yes K Severe 2 < 48 hrs Large Yes L Severe 2 < 48 hrs Large Yes Mean percentage reduction in tumour volume was 42% (W = 0, significant at p < 0.05; W = Wilcoxon test statistic) (Table 3 ) . In all applicable pathology specimens, no residual giant cells were identified in the final pathology analysis. Table 3 Specimen pathology results, volumetric response to Denosumab treatment Patient Tumour volume pre Denoumab (cm^3) Tumour volume post Denosumab (cm^3) Reduction in tumour volume (%) Final pathology report A 95.6 66.7 30 Complete response. No giant cells. B 8.2 2.2 73 No giant cells. No evidence of malignancy. C 39.3 24.4 38 Complete response. No giant cells. D 49.5 21.5 57 Complete response. No giant cells. E 1269.7 1095.5 14 Complete response. No giant cells. F 342.7 257.9 25 No giant cells G 35.8 33.3 7 No giant cells H 362.1 211 42 No tumour identified on further biopsy (no surgery) I 23.5 7.1 70 N/A J 10.4 6 42 No giant cells K 97.2 25.7 74 Awaiting surgery L 72.9 51.8 29 Awaiting surgery Seven out of 12 cases demonstrated an improvement in the Bilsky grade. (Table 4 , Fig. 2 ). An improvement was seen in the WBB layers/sectors in 3/12 cases, and these all correlated with the most significant improvements in Bilsky grade. In 6/12 cases the WBB layers/sectors were unaffected. Median baseline SUVmax was 14.7, median SUVmax post treatment was 3.3 (W = 0, significant at p < 0.05; W, Wilcoxon test statistic). Eight out of 12 patients demonstrated a positive calcification response to Denosumab with intra lesional bone formation (Fig. 2 ). Appropriate imaging was not available to assess this in two patients. Table 4 Tumour characteristics before and after Denosumab treatment (W-B-B layers recorded at presentation). Patient Epidural disease (Bilsky) Pre Post W-B-B layers / Sectors Pre Post PET SUV capitation Pre Post % reduction (PET SUV) Calcification response (Boriani) A 3 1c 3–12, A - D 3–12, A - D 15.8 14.1 10.8 2a B 1b 1b 4–9, A - D 4–9, A – D 13.4 Normal marrow n/a 2a C 2 1b 6–10, A - D 6–10, A – E 17.7 6.2 65 1b D 3 1b 2–10, A - D 3–10, A – D 14.7 6.9 53 1a E N/A N/A N/A N/A 16.4 7.3 55.5 2a F 3 1b 12–10, A - D 1–9, A – D 11.6 Normal marrow n/a 2a G 1c 1c 4–9, A - D 4–9, A – D 9 Normal marrow n/a 2b H 3 3 SACRAL, N/A SACRAL, N/A 16.3 4.4 73 2b I 3 1c 7–1, A – D 7–12, A - D Data not available 2.9 n/a 2a J 1c 1a 5–10, A - D 5–10, A - D 11.8 3.6 69 n/a K 3 1b 1–12, F (A – D + VERT) 1–12 F (A – D + VERT) 25.9 2.9 89 2a L 2 2 2–11, A - D 2–11, A - D 14.2 1.5 89 n/a Median baseline SUVmax = 14.7, median SUVmax post treatment = 3.3 In all cases where the pathology data was available, surgical margins were wide. (Table 5 ). No intraoperative adverse events were noted. Mean blood loss in cases for which the information was available (6 cases) was 2655ml. One case of recurrence was recorded following temporary cessation of denosumab. The tumour receded once again following reinstatement of treatment and underwent subsequent proton therapy. At one year follow up, there were no cases of local disease recurrence, malignant transformation or metastases. No adverse side effects of Denosumab treatment were observed. Table 5 Operative data Patient Resection Surgical time (Hrs) Surgical Margin Blood loss (ml) A En bloc T11 – L1 12 hrs 40 mins INA 3656 B En Bloc C7 10 hrs 50 mins Wide 3768 C En Bloc L2 9 hrs 2 mins INA 2100 D En Bloc C7 –T1 10 hrs 55 mins Wide 648 E En Bloc sacropelvis (complete) INA Wide (iliac & sacral) INA F En Bloc L1 INA Wide 3655 G En Bloc T8 INA INA INA H n/a n/a n/a n/a I n/a n/a n/a n/a J En bloc T6 10 hrs 20 mins Wide 2100 K n/a n/a n/a n/a L n/a n/a n/a n/a INA: information not available Discussion This study offers one of the first large case series of spinal GCT treated with neo – adjuvant Denosumab. The main finding is the tumour radiological improvement following denosumab treatment in terms of mean percentage reduction in tumour volume of 42% and median baseline SUVmax reduction from 14.7 pre - treatment to 3.3 post - treatment. Also, following treatment, 8/12 patients demonstrated intra – lesional bone formation. Secondarily, seventy-five percent of patients were pain free following treatment with 58% of patients showing improvement within 48 hours. Following Denosumab treatment our data demonstrated a significant percentage reduction in tumour volume (W = 0, significant at p < 0.05; W, Wilcoxon test statistic). Mean percentage reduction in tumour volume was 42%. A correlation was demonstrated between initial tumour volume and percentage reduction in tumour size, with larger tumours undergoing a smaller volumetric reduction (Pearson coefficient − 0.44). This is perhaps unsurprising given the uniform dosing regimen regardless of initial tumour size. However a previous study which characterised population pharmacokinetics of denosumab in patients with advanced solid tumours and bone metastases noted that following 120mg dosing every 4 weeks, as was the case in our study, RANKL occupancy exceeded 97% during the entire dosing interval and concluded dosage adjustments based on body weight, age, race and tumour type is not necessary in these patients [ 17 ]. Nonetheless Denosumab clearly effected a significant reduction in tumour volume in these cases, facilitating subsequent En Bloc resection with no adverse events occurring during the treatment of patients in this case series. Improvement in Bilsky grade was observed in 7/12 cases (Fig. 2 ). In the rest of the cases, the Bilsky grade remained the same. The improvements in Bilsky grade correlated with an improvement in neurological status in these patients. The change in Bilsky grade does not therefore appear to be as dramatic as the reduction in tumour volume noted but again this is perhaps unsurprising given that it is a two - dimensional grading system, and also that epidural disease may only represent a relatively small fraction of the total tumour volume. Furthermore, the most significant neurological improvement following treatment was a patient who regained ability to ambulate but there was no overall change in Bilsky grade following treatment, suggesting clinical response can be observed without radiological response. Our results nonetheless confirm that treatment either halted disease progression or effected an improvement in all cases. W – B – B layers / sectors improved in 3/12 cases and these improvements correlated with the most profound changes in Bilsky grade and each had large percentage volumetric reduction. Similarly, this less profound effect on the WBB layers is likely representative of the larger overall tumour volume represented by this system. The cases in which the WBB layers/sectors remained the same nonetheless showed a good calcification response (2a or 2b) demonstrating that denosumab did still have a beneficial effect in these cases. Pathology reports confirmed wide excision in all applicable patient specimens. Three patients had not finished treatment and was awaiting surgery at the time of writing, one of which was delayed secondary to COVID-19. This exceeds success of the previously referenced study [ 12 ] and provides further robust evidence for neo – adjuvant use. An area of debate in the reported literature concerns the duration of Denosumab use. Our data supports the conclusion made by Boriani et al that if following en bloc resection, margins are confirmed as tumour – free, denosumab can be discontinued post operatively [ 6 ]. PET standardised uptake values confirmed efficacy of Denosumab treatment in reducing metabolic activity (W = 0, significant at p < 0.05; W = Wilcoxon test statistic), in 3/11 cases to normal marrow values (one patient has not, at the time of writing, had a follow up PET). Median baseline SUVmax was 14.7, median SUVmax post treatment was 3.3. This result is commensurate with the available published literature and further confirms that reduced PET avidity appears to be an early sign of response to Denosumab treatment and a useful tool in its assessment [18 [ 19 ]. Calcification response in our patient cohort demonstrated good response to Denosumab therapy, with 8/12 patients demonstrating subsequent intra lesional bone formation. One question that our study does not answer is how long should Denosumab treatment last as stand - alone therapy, as the majority (8/12) of patients underwent En Bloc resection following initial treatment. In one patient treated as stand – alone therapy, treatment was stopped due to pregnancy after 20 months. Following cessation, the tumour started to grow once again and then re - receded after re – commencement of therapy. In a preliminary report of 12 cases and literature review in 2020, Boriani et al noted a radiological withdrawal effect in one case with disappearance of the sclerotic rim and core ossification following 15 months of treatment when treatment was stopped [ 6 ]. Previous studies have also lacked long term follow up, or reported on patients still undergoing Denosumab treatment [ 10 ] [ 20 ] and therefore the results from these studies must be interpreted cautiously [ 21 ]. In a prospective non randomised study of neo-adjuvant Denosumab treatment for GCT in multiple sites including long bones, Traub et al also noted that the change in the tumour characteristics, from soft tumour to fibro osseous matrix following Denosumab made accurately finding the junction between treated tumour and normal bone difficult, and furthermore speculated that tumour cells may become trapped within the thickened cortical and subchondral bone produced by Denosumab and contribute to local recurrence [ 22 ]. Clearly this possibility needs to be carefully considered when planning en - bloc resection. Our results clearly demonstrate that neo – adjuvant Denosumab effects a significant improvement in pain in the neo – adjuvant setting. Pre – treatment, all but one patient were experiencing moderate to severe pain which in had been present on average for 6 months. Following treatment with Denosumab, 75% (9/12) of patients reported being pain free, with 58% (7/12) describing a ‘large’ improvement in their symptoms. Perhaps most striking, however, is the rapidity with which Denosumab took effect in selected cases. In 58% (7/12) of cases, improvement in symptoms was noted within 48 hours. Interestingly, this effect is not uniform, and the remainder of patients took 6 weeks or more to effect improvement. Nonetheless, although the time taken effect pain relief differed, in most cases the end point was the same: neo – adjuvant treatment with Denosumab improved pain significantly. Only 1 patient described the improvement as ‘mild’, and this case had mild symptoms at presentation. Current available studies do not, to the authors knowledge, report on improvement in pain symptoms exclusively in GCT of the spine following Denosumab treatment. There are several studies in GCT of mixed location (long bones, spine, pelvis) which report an improvement in pain symptoms following treatment and to this end corroborate the findings of our study. The study by Traub et al reported significant pain relief in all patients after 1 month and complete pain relief in 80% of patients at 6 months [ 22 ]. A prospective phase II study of the effects of Denosumab treatment on pain for GCT of the bone across all sites reported Denosumab to be effective in reducing pain in both resectable and unresectable GCT with rapid and clinically relevant improvement in symptoms in both groups [ 23 ]. It is worth noting that Denosumab therapy does carry additional risks. Osteonecrosis of the jaw, hypocalcemia, hypophosphataemia and rebound – associated vertebral fractures are among the most common adverse side effects reported following its use and patients need to be carefully monitored for this during treatment [ 20 ] [ 24 ][ 25 ]. Limitations Our study had several limitations. As a single centre study, the case series is small and therefore the statistical significance of the results is limited. A multi-centre trial is required to generate an adequately powered study. There was no control group and hence no baseline for determining the effectiveness of the study treatment, although such a control group may raise ethical issues in a study such as this. Furthermore, there were no long-term outcome measures in the study, such as disease-free survival, long term pain relief, as the requisite follow up for inclusion in the study was 6 months. Finally, the pain scoring system was subjective and not validated. Despite these limitations we believe the study results provide good evidence of the beneficial effect of neo – adjuvant Denosumab in this setting which adds to the limited current available literature on the topic. Conclusion This study attempted to answer the question of whether denosumab is an effective neo – adjuvant treatment for GCT of the spine. Our results have shown that treatment significantly improves pain in the majority of patients, and effects pre–operative reduction in tumour volume and new bone formation. Metabolic activity is also significantly reduced. These factors facilitate en bloc resection of the tumour and reduces the likelihood of intra - operative morbidity. We would therefore recommend routine use when W-B-B – based criteria are fulfilled for en – bloc excision. Assuming that margins are disease – free following surgery, we advocate cessation of treatment post – operatively. Declarations Ethics approval and consent to participate: our institutional review board approved this study Consent for publication: not applicable Availability of data and materials: All data generated or analysed during this study are included in this published article Competing interests: The authors declare they have no competing interests Funding: not applicable Authors contributions: NBC collected and analysed data and wrote manuscript. CD analysed data and contributed to manuscript editing. GM collected and analysed data and contributed to manuscript editing. JJR collected and analysed data, contributed to manuscript editing, and was senior author. All authors read and approved the final manuscript. Acknowledgements: not applicable. References Luther N, Bilsky M, Hartl R; Giant Cell Tumour of the Spine; Neurosurg Clinc N Am 19 (2008) 49–55 Luksanapruksa et al; Management of spinal giant cell tumours; Spine J 2016 Feb;16(2):259–69 Raskin K et al; Giant Cell Tumour of the Bone; J Am Acad Orthop Surg 2013; 21: 118–126 Harrop et al; Aggressive ‘Benign’ primary spine neoplasms; Spine, 34 (22S); S39 – S47, 2009 Charest – Morin et al; En bloc resection versus intralesional surgery in the treatment of giant cell tumour of the spine. Spine 42(18):1383–1390 Boriani et al; Denosumab in the treatment of giant cell tumour of the spine. Preliminary report, review of the literature and protocol proposal; Eur Spine J 2020 Feb; 29(2):257–271 Leggon RE, Zlotecki R, Reith J, et al. Giant cell tumor of the pelvis and sacrum: 17 cases and analysis of the literature. Clin Orthop Relat Res 2004; 423:196–207 Lin et al; Long term follow up of patients with giant cell tumour of the sacrum treated with selective arterial embolization; Cancer 2002;95:1317–25 Branstetter DG, Nelson SD, Manivel JC, et al. Denosumab Induces Tumor Reduction and Bone Formation in Patients with Giant-Cell Tumor of Bone. Clinical Cancer Research. 2012;18(16):4415–4424. doi: 10.1158/1078-0432.CCR-12-0578 . Thomas D, Henshaw R, Skubitz K, Chawla S, Staddon A, Blay JY, et al. Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study. Lancet Oncol 2010;11:275–80 Lewin J, Thomas D. Denosumab: a new treatment option for giant cell tumor of bone. Drugs Today 2013;49:693–700. Goldschlager T, Dea N, Boyd M, et al. Giant cell tumors of the spine: has denosumab changed the treatment paradigm? J Neurosurg Spine. 2017;91:526–533. Chen et al; Therapeutic benefits of neo- adjuvant and post – operative Denosumab on sacral giant cell tumour: a retrospective cohort study of 30 cases; JBUONMar-Apr 2018;23(2):453–459 Bilsky M et al; Reliability analysis of the epidural spinal cord compression scale J Neurosurg spine. 2010 Sep; 13(3):324–8 Boriani, S et al., Spine, 22, 1036–1044, 1997 Enneking WF. A system of staging musculoskeletal neoplasms. Clin Orthop Relat Res. 1986; (204):9–24 Gibiansky L et al; Population pharmacokinetics analysis of denosumab in patients with bone metastases from solid tumours; Clin Pharmacokinet 2012 Apr 1;51(4):247 – 60 18.: Engellau et al; Assessmenrt of Denosumab treatment effects and imagine response in patients with giant cell tumour of bone. World J Surg Oncol. 2018 19.: Boye K et al; Denosumab in patients with giant cell tumour of bone in Norway: results from a nationwide cohort; Acta Oncol. 2017. Chawla S, Henshaw R, Seeger L, Choy E, Blay JY, Ferrari S, Kroep J, Grimer R, Reichardt P, Rutkowski P et al (2013) Safety and efficacy of denosumab for adults and skeletally mature adoles- cents with giant cell tumour of bone: interim analysis of an open- label, parallel-group, phase 2 study. Lancet Oncol 14:901–908 Errani C, Tsukamoto S, Mavrogenis A. How safe and effective is denosumab for bone giant cell tumour? Int Orthop. 2017. Nov; 41(11): 2397–2400; Traub et al. Efficacy of Denosumab in joint preservation for patients with giant cell tumour of the bone. Eur J Cancer. 2016 May. 59: 1–12. Martin-Broto J et al. Effects of Denosumab on pain and analgesic use in giant cell tumour of bone: interim results from a phase II study. Acta Oncol. 2014 Sep; 53(9): 1173–9 Manzaneque A, Chaguaceda C, Mensa M, Bastida C, Creus-Baró N (2017) Use and safety of denosumab in cancer patients. Int J Clin Pharm 39(3):522–526. Popp AW, Zysset PK, Lippuner K (2016) Rebound-associated ver- tebral fractures after discontinuation of denosumab—from clinic and biomechanics. Osteoporos Int 27:1917–1921 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2405951","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":162341164,"identity":"45dde844-d6af-4818-8d18-716261ad7b27","order_by":0,"name":"Nicolas Beresford-Cleary","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+klEQVRIiWNgGAWjYBACg8MMzMwfamx4+BkSUCQSsCoHAQuQFoljaXKSDUBFB4jRYnMAqIW36bCxwQGitRxnfmws2ZCWuPl48sHPHyru2TOw9z5+wdiWhlOL2WE24+SPDTaJ2848S5Y4cKY4sYHnuJkFY1sOHi08zIdBtmy7kWPGcLAtIYFBIo3NgLGtAqcWY5AW3obDiZtnQLTYE9RiCNSSDPa+BEQLY4NEGvMDfA4zBPrFGBTIEiC/nDmTkNjGc4yNIeEcbu8bnD/8WBocle3JBz9UVCTY87O3MX/4UJaMUwsmYAMiiQQSNIAB8wdSdYyCUTAKRsGwBgDTSFebWbQTVAAAAABJRU5ErkJggg==","orcid":"","institution":"Oxford University Hospitals","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Nicolas","middleName":"","lastName":"Beresford-Cleary","suffix":""},{"id":162341166,"identity":"cf570b46-5b82-4a09-acaa-b855ebc3c157","order_by":1,"name":"Charlotte Dandurand","email":"","orcid":"","institution":"Vancouver General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Charlotte","middleName":"","lastName":"Dandurand","suffix":""},{"id":162341167,"identity":"1b8ca47d-9e99-464a-b31d-99616aec1c27","order_by":2,"name":"Gerard Mawhinney","email":"","orcid":"","institution":"University of Oxford","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Gerard","middleName":"","lastName":"Mawhinney","suffix":""},{"id":162341168,"identity":"a6c411b8-3694-4291-a7f1-24f2acdd40db","order_by":3,"name":"Jeremy Reynolds","email":"","orcid":"","institution":"Oxford University Hospitals","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jeremy","middleName":"","lastName":"Reynolds","suffix":""}],"badges":[],"createdAt":"2022-12-22 16:14:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2405951/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2405951/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":30894535,"identity":"029bfcbd-ba13-4c2c-aa68-5fa006894dc6","added_by":"auto","created_at":"2022-12-29 17:09:00","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":345174,"visible":true,"origin":"","legend":"\u003cp\u003eProposed radiological classification of GCT, used to evaluate Denosumab effectiveness [6]\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-2405951/v1/aa619a8e0528f6728076c338.png"},{"id":30894536,"identity":"7450f507-0d4f-4f59-957a-5b7c99194429","added_by":"auto","created_at":"2022-12-29 17:09:00","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":603711,"visible":true,"origin":"","legend":"\u003cp\u003eT12 GCT. A: pre – treatment b: post – treatment (1 cycle), demonstrating sclerosis and reduction in epidural disease\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-2405951/v1/e4b6ad4afce104b916bb9dc2.png"},{"id":30896103,"identity":"708a72cc-4aca-4c34-ac2d-2fa3dc7644a9","added_by":"auto","created_at":"2022-12-29 17:17:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1093832,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2405951/v1/64f477f4-db2c-4759-a306-dd0d1f4bb07e.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eThe Use of Neo – Adjuvant Denosumab in Treatment of Giant Cell Tumours of the Spine\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eGiant cell tumours (GCTs) are osteolytic lesions that occur most frequently in the long bones. In the axial spine they most commonly involve the sacrum, and in the mobile spine the vertebral bodies, but can also involve the posterior elements, discs and paraspinal soft tissue [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. They are locally aggressive and can be large at presentation. Typical presentation is with pain which often precedes diagnosis. Up to 72% of patients also experience neurological symptoms such as radiculopathy or symptoms of cord or cauda equina compression [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. They commonly occur in patients aged 20\u0026ndash;40 years, with a female \u0026ndash; to \u0026ndash; male ratio of 1.2:1 [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDespite being classified as a benign lesion, GCT can show malignant behaviour. Typical metastasis is via haematogenous spread to the lungs and occurs in 2\u0026ndash;3% of cases. A small number may undergo sarcomatous change, most often to osteosarcoma, which can occur as a primary malignant GCT or more commonly as secondary malignancy after radiotherapy [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTreatment options include therapeutic embolisation, radiotherapy alone, intralesional surgery +/- radiotherapy and en bloc resection. Of these, en bloc resection is considered the Enneking appropriate treatment [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e][\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e][\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Surgical resection margins remain the best predictors of recurrence, and though intralesional resection may spare neural, bony and visceral structures, it does so at the cost of an increased risk of local recurrence, with rates up to 46% reported [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Radiotherapy alone and therapeutic embolization are associated with unacceptably high local recurrence rates [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e][\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. En bloc resection gives the lowest chance of local recurrence and improves survival, but risks increased inter \u0026ndash; operative and functional morbidity and may be unachievable due to anatomical constraints [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e][\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWith the goal of facilitating en bloc resection, interest has grown in the role of denosumab in the neo \u0026ndash; adjuvant setting. Denosumab is a human monocloncal antibody that reduces osteoclast activity by binding receptor of activator nuclear factor kappa \u0026ndash; B ligand (RANKL). It has previously been shown to be effective in suppressing bone destruction in patients with multiple myeloma and bony metastases in solid tumours such as breast and prostate [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In 2010 Thomas et al conducted an open label phase 2 study investigating the effect of Denosumab on tumour cell survival and growth on 37 patients with recurrent or unresectable GCT. Eighty \u0026ndash; six percent of patients had a tumour response defined as either elimination of at least 90% of giant cells, or no radiological progression of the target lesion up to week 25 [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. A subsequent study of the histologic analyses of the samples taken, Branstetter et al concluded that in addition to significantly reducing or eliminating RANK positive tumour giant cells, Denosumab also reduced the content of tumour stromal cells and replaced them with nonproliferative, differentiated, densely woven new bone [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Multiple studies to date have demonstrated its efficacy in controlling surgically unresectable GCTs, and approval for its use was granted by the FDA in 2013 [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e][\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In 2015 Goldschlager et al reported on a series of 5 patients treated pre \u0026ndash; operatively with Denosumab for GCT of the spine, and demonstrated a 100% radiological response to treatment, although one patient failed to demonstrate a histological response [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Despite these promising results, further evidence for the use of Denosumab in the neo \u0026ndash; adjuvant setting is required.\u003c/p\u003e \u003cp\u003eIntrusive pain is very common in these patients, and is observed to improve with Denosumab treatment, but there remains a paucity of evidence on this aspect of therapy. Nonetheless, the published literature that does exist is encouraging, with rates of improvement in pain of up to 80% reported when used in the neo \u0026ndash; adjuvant setting [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis study aimed to investigate the efficacy and safety of Denosumab when used in the neo \u0026ndash; adjuvant setting in terms of improving tumour radiological characteristics for en bloc resection and symptom relief.\u003c/p\u003e \u003cp\u003eWe performed a retrospective study of prospectively collected data on 12 patients treated with neo \u0026ndash; adjuvant Denosumab for GCT of the spine in a tertiary referral centre. The institutional review board approved the study.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient population\u003c/h2\u003e \u003cp\u003eInclusion criteria were: patients were 18 years or older at the time of treatment, had a primary diagnosis of biopsy \u0026ndash; confirmed GCT of the mobile spine or sacrum, had received Denosumab as a primary or neo \u0026ndash; adjuvant treatment, and had a minimum follow \u0026ndash; up of 6 months after initiation of Denosumab treatment. Cases of recurrent GCT were excluded from the study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eData collection\u003c/h2\u003e \u003cp\u003ePatient demographic data was collected such as age, sex, and ethnicity. Clinical presentation was collected including pain severity and neurological status, duration of symptoms and previous treatment. Pain severity was graded as mild, moderate or severe. Details of the Denosumab treatment regimen were included, as well as duration of treatment. Patients were contacted directly, and a record was taken of the reported time taken for significant symptom improvement (\u0026lt;\u0026thinsp;48hr, 1 week, 6 weeks, \u0026gt;\u0026thinsp;6 weeks), patient \u0026ndash; reported degree of symptom improvement (mild, moderate, large), and whether Denosumab effected complete resolution of symptoms. Surgical data was collected including type of surgical resection, surgical time and intraoperative blood loss. Final pathology reports were reviewed for final surgical margins and presence of tumoral cell giant cells and response to treatment. Intraoperative and postoperative adverse events (AEs) were collected. The details of the denosumab regimen were collected including duration, posology and denosumab related AEs. Outcomes were collected including tumour recurrence, progression, metastasis and malignant transformation. Tumour measurements based on imaging were collected at 3-month time intervals following Denosumab initiation and continued depending on duration of treatment. Volumetric analysis was performed based on these measurements. The Bilsky classification for epidural disease [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] as well as the Weinstein-Boriani-Biagini layers and sectors [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] and also Enneking staging [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] were recorded. The Boriani classification for Denosumab calcification response (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] was also noted. PET SUV capitation was measured to assess treatment response. Clinical response would be determined by volumetric reduction in tumour size, PET SUV capitation, the Boriani Classification and improvement in pain symptoms.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e(Tables follow references)\u003c/p\u003e \u003cp\u003e12 patients were included in the study, 5 males, 7 females (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Mean age was 38.1 years (11.8 years). Ten patients were Caucasian British, 1 Caucasian Romanian, 1 Pakistani British.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical presentation, severity of pain, neurological status and symptoms duration.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eClinical presentation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePain severity at presentation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNeurological status at presentation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSymptom duration at presentation (months)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBack pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIntact\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNeck pain \u0026amp; b/l UL radicular pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIntact\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLBP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIntact\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eThoracic \u0026amp; RUL radicular pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMild\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIntact\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLeft iliac crest pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIntact\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eData not available\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLBP\u0026thinsp;+\u0026thinsp;b/l LL radicular pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSevere\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIntact\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLBP, left LL radicular pain, sphincter disturbance\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSevere\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSphincter disturbance, unspecified\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePain: 15\u003c/p\u003e \u003cp\u003eSphincter disturbance: 3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLeft LL radiculopathy, perineal pain \u0026amp; dysaesthesias\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSevere\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eUnable to walk; bladder/bowel incontinence at presentation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePain: 4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eThoracic pain, bladder/bowel disturbance\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSevere\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eThoracic myelopathy, gait/bladder/bowel disturbance (non specific)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eData not available\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eThoracic pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSevere\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eData not available\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eData not available\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eK\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCervical pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSevere\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eC6 ASIA D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eThoracic pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSevere\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIntact\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eUL: Upper Limb LL: Lower Limb b/l: Bilateral\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eMean duration of pain at presentation was 5.8 months (3.9 months). This information was not available for 3 patients. Treatment regimen with Denosumab was uniform for all patients and comprised weekly administration on days 1, 8 and 15, and then monthly thereafter. Mean duration of treatment was 8.2 months (10 months).\u003c/p\u003e \u003cp\u003eNine out of 12 patients were pain free following treatment (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cb\u003e).\u003c/b\u003e Seven out of 12 patients reported significant improvement in pain within 48 hours.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSymptom response\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePain severity at presentation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDuration of tx (months)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTime until significant symptom improvement\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDegree of symptom improvement\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePain free post Denosumab treatment?\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;6 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;48 hrs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLarge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMild\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;6 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMild\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;48 hrs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLarge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSevere\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;48 hrs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLarge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSevere\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;6 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSevere\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39 (20\u0026thinsp;+\u0026thinsp;19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;48 hrs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLarge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSevere\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSevere\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;48 hrs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLarge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eK\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSevere\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;48 hrs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLarge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSevere\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;48 hrs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLarge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eMean percentage reduction in tumour volume was 42% (W\u0026thinsp;=\u0026thinsp;0, significant at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05; W\u0026thinsp;=\u0026thinsp;Wilcoxon test statistic) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. In all applicable pathology specimens, no residual giant cells were identified in the final pathology analysis.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSpecimen pathology results, volumetric response to Denosumab treatment\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTumour volume pre Denoumab (cm^3)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTumour volume post Denosumab (cm^3)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eReduction in tumour volume (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFinal pathology report\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e95.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eComplete response. No giant cells.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo giant cells. No evidence of malignancy.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e39.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eComplete response. No giant cells.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e49.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eComplete response. No giant cells.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1269.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1095.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eComplete response. No giant cells.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e342.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e257.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo giant cells\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e35.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo giant cells\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e362.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e211\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo tumour identified on further biopsy (no surgery)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo giant cells\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eK\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e97.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAwaiting surgery\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e72.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e51.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAwaiting surgery\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eSeven out of 12 cases demonstrated an improvement in the Bilsky grade. (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). An improvement was seen in the WBB layers/sectors in 3/12 cases, and these all correlated with the most significant improvements in Bilsky grade. In 6/12 cases the WBB layers/sectors were unaffected. Median baseline SUVmax was 14.7, median SUVmax post treatment was 3.3 (W\u0026thinsp;=\u0026thinsp;0, significant at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05; W, Wilcoxon test statistic). Eight out of 12 patients demonstrated a positive calcification response to Denosumab with intra lesional bone formation (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Appropriate imaging was not available to assess this in two patients.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTumour characteristics before and after Denosumab treatment (W-B-B layers recorded at presentation).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eEpidural disease\u003c/p\u003e \u003cp\u003e(Bilsky)\u003c/p\u003e \u003cp\u003ePre Post\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eW-B-B layers /\u003c/p\u003e \u003cp\u003eSectors\u003c/p\u003e \u003cp\u003ePre Post\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003ePET SUV capitation\u003c/p\u003e \u003cp\u003ePre Post\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e% reduction (PET SUV)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eCalcification response (Boriani)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1c\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u0026ndash;12, A - D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3\u0026ndash;12,\u003c/p\u003e \u003cp\u003eA - D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e14.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e10.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2a\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u0026ndash;9,\u003c/p\u003e \u003cp\u003eA - D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u0026ndash;9, A \u0026ndash; D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e13.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNormal marrow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003en/a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2a\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6\u0026ndash;10,\u003c/p\u003e \u003cp\u003eA - D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6\u0026ndash;10,\u003c/p\u003e \u003cp\u003eA \u0026ndash; E\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e17.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1b\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u0026ndash;10,\u003c/p\u003e \u003cp\u003eA - D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3\u0026ndash;10,\u003c/p\u003e \u003cp\u003eA \u0026ndash; D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e14.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1a\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e16.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e55.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2a\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12\u0026ndash;10,\u003c/p\u003e \u003cp\u003eA - D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u0026ndash;9,\u003c/p\u003e \u003cp\u003eA \u0026ndash; D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNormal marrow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003en/a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2a\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1c\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1c\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u0026ndash;9,\u003c/p\u003e \u003cp\u003eA - D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u0026ndash;9, A \u0026ndash; D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNormal marrow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003en/a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2b\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSACRAL, N/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSACRAL, N/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e16.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2b\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1c\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7\u0026ndash;1,\u003c/p\u003e \u003cp\u003eA \u0026ndash; D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7\u0026ndash;12, A - D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eData not available\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003en/a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2a\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1c\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u0026ndash;10,\u003c/p\u003e \u003cp\u003eA - D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5\u0026ndash;10,\u003c/p\u003e \u003cp\u003eA - D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003en/a\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eK\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u0026ndash;12, F (A \u0026ndash; D\u0026thinsp;+\u0026thinsp;VERT)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u0026ndash;12 F (A \u0026ndash; D\u0026thinsp;+\u0026thinsp;VERT)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e25.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2a\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u0026ndash;11,\u003c/p\u003e \u003cp\u003eA - D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2\u0026ndash;11, A - D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e14.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003en/a\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003eMedian baseline SUVmax\u0026thinsp;=\u0026thinsp;14.7, median SUVmax post treatment\u0026thinsp;=\u0026thinsp;3.3\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn all cases where the pathology data was available, surgical margins were wide. (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e\u003cb\u003e).\u003c/b\u003e No intraoperative adverse events were noted. Mean blood loss in cases for which the information was available (6 cases) was 2655ml. One case of recurrence was recorded following temporary cessation of denosumab. The tumour receded once again following reinstatement of treatment and underwent subsequent proton therapy. At one year follow up, there were no cases of local disease recurrence, malignant transformation or metastases. No adverse side effects of Denosumab treatment were observed.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eOperative data\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eResection\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSurgical time (Hrs)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSurgical Margin\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBlood loss (ml)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEn bloc T11 \u0026ndash; L1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 hrs 40 mins\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eINA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3656\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEn Bloc C7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 hrs 50 mins\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3768\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEn Bloc L2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 hrs 2 mins\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eINA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEn Bloc C7 \u0026ndash;T1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 hrs 55 mins\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e648\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEn Bloc sacropelvis (complete)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eINA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWide (iliac \u0026amp; sacral)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eINA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEn Bloc L1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eINA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3655\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEn Bloc T8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eINA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eINA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eINA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en/a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en/a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en/a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003en/a\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en/a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en/a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en/a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003en/a\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEn bloc T6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 hrs 20 mins\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eK\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en/a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en/a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en/a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003en/a\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en/a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en/a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en/a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003en/a\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eINA: information not available\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study offers one of the first large case series of spinal GCT treated with neo \u0026ndash; adjuvant Denosumab. The main finding is the tumour radiological improvement following denosumab treatment in terms of mean percentage reduction in tumour volume of 42% and median baseline SUVmax reduction from 14.7 pre - treatment to 3.3 post - treatment. Also, following treatment, 8/12 patients demonstrated intra \u0026ndash; lesional bone formation. Secondarily, seventy-five percent of patients were pain free following treatment with 58% of patients showing improvement within 48 hours.\u003c/p\u003e \u003cp\u003eFollowing Denosumab treatment our data demonstrated a significant percentage reduction in tumour volume (W\u0026thinsp;=\u0026thinsp;0, significant at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05; W, Wilcoxon test statistic). Mean percentage reduction in tumour volume was 42%. A correlation was demonstrated between initial tumour volume and percentage reduction in tumour size, with larger tumours undergoing a smaller volumetric reduction (Pearson coefficient \u0026minus;\u0026thinsp;0.44). This is perhaps unsurprising given the uniform dosing regimen regardless of initial tumour size. However a previous study which characterised population pharmacokinetics of denosumab in patients with advanced solid tumours and bone metastases noted that following 120mg dosing every 4 weeks, as was the case in our study, RANKL occupancy exceeded 97% during the entire dosing interval and concluded dosage adjustments based on body weight, age, race and tumour type is not necessary in these patients [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Nonetheless Denosumab clearly effected a significant reduction in tumour volume in these cases, facilitating subsequent En Bloc resection with no adverse events occurring during the treatment of patients in this case series.\u003c/p\u003e \u003cp\u003eImprovement in Bilsky grade was observed in 7/12 cases (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In the rest of the cases, the Bilsky grade remained the same. The improvements in Bilsky grade correlated with an improvement in neurological status in these patients. The change in Bilsky grade does not therefore appear to be as dramatic as the reduction in tumour volume noted but again this is perhaps unsurprising given that it is a two - dimensional grading system, and also that epidural disease may only represent a relatively small fraction of the total tumour volume. Furthermore, the most significant neurological improvement following treatment was a patient who regained ability to ambulate but there was no overall change in Bilsky grade following treatment, suggesting clinical response can be observed without radiological response. Our results nonetheless confirm that treatment either halted disease progression or effected an improvement in all cases. W \u0026ndash; B \u0026ndash; B layers / sectors improved in 3/12 cases and these improvements correlated with the most profound changes in Bilsky grade and each had large percentage volumetric reduction. Similarly, this less profound effect on the WBB layers is likely representative of the larger overall tumour volume represented by this system. The cases in which the WBB layers/sectors remained the same nonetheless showed a good calcification response (2a or 2b) demonstrating that denosumab did still have a beneficial effect in these cases.\u003c/p\u003e \u003cp\u003ePathology reports confirmed wide excision in all applicable patient specimens. Three patients had not finished treatment and was awaiting surgery at the time of writing, one of which was delayed secondary to COVID-19. This exceeds success of the previously referenced study [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] and provides further robust evidence for neo \u0026ndash; adjuvant use. An area of debate in the reported literature concerns the duration of Denosumab use. Our data supports the conclusion made by Boriani et al that if following en bloc resection, margins are confirmed as tumour \u0026ndash; free, denosumab can be discontinued post operatively [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePET standardised uptake values confirmed efficacy of Denosumab treatment in reducing metabolic activity (W\u0026thinsp;=\u0026thinsp;0, significant at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05; W\u0026thinsp;=\u0026thinsp;Wilcoxon test statistic), in 3/11 cases to normal marrow values (one patient has not, at the time of writing, had a follow up PET). Median baseline SUVmax was 14.7, median SUVmax post treatment was 3.3. This result is commensurate with the available published literature and further confirms that reduced PET avidity appears to be an early sign of response to Denosumab treatment and a useful tool in its assessment [18 [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCalcification response in our patient cohort demonstrated good response to Denosumab therapy, with 8/12 patients demonstrating subsequent intra lesional bone formation. One question that our study does not answer is how long should Denosumab treatment last as stand - alone therapy, as the majority (8/12) of patients underwent En Bloc resection following initial treatment. In one patient treated as stand \u0026ndash; alone therapy, treatment was stopped due to pregnancy after 20 months. Following cessation, the tumour started to grow once again and then re - receded after re \u0026ndash; commencement of therapy. In a preliminary report of 12 cases and literature review in 2020, Boriani et al noted a radiological withdrawal effect in one case with disappearance of the sclerotic rim and core ossification following 15 months of treatment when treatment was stopped [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Previous studies have also lacked long term follow up, or reported on patients still undergoing Denosumab treatment [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] and therefore the results from these studies must be interpreted cautiously [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In a prospective non randomised study of neo-adjuvant Denosumab treatment for GCT in multiple sites including long bones, Traub et al also noted that the change in the tumour characteristics, from soft tumour to fibro osseous matrix following Denosumab made accurately finding the junction between treated tumour and normal bone difficult, and furthermore speculated that tumour cells may become trapped within the thickened cortical and subchondral bone produced by Denosumab and contribute to local recurrence [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Clearly this possibility needs to be carefully considered when planning en - bloc resection.\u003c/p\u003e \u003cp\u003eOur results clearly demonstrate that neo \u0026ndash; adjuvant Denosumab effects a significant improvement in pain in the neo \u0026ndash; adjuvant setting. Pre \u0026ndash; treatment, all but one patient were experiencing moderate to severe pain which in had been present on average for 6 months. Following treatment with Denosumab, 75% (9/12) of patients reported being pain free, with 58% (7/12) describing a \u0026lsquo;large\u0026rsquo; improvement in their symptoms. Perhaps most striking, however, is the rapidity with which Denosumab took effect in selected cases. In 58% (7/12) of cases, improvement in symptoms was noted within 48 hours. Interestingly, this effect is not uniform, and the remainder of patients took 6 weeks or more to effect improvement. Nonetheless, although the time taken effect pain relief differed, in most cases the end point was the same: neo \u0026ndash; adjuvant treatment with Denosumab improved pain significantly. Only 1 patient described the improvement as \u0026lsquo;mild\u0026rsquo;, and this case had mild symptoms at presentation. Current available studies do not, to the authors knowledge, report on improvement in pain symptoms exclusively in GCT of the spine following Denosumab treatment. There are several studies in GCT of mixed location (long bones, spine, pelvis) which report an improvement in pain symptoms following treatment and to this end corroborate the findings of our study. The study by Traub et al reported significant pain relief in all patients after 1 month and complete pain relief in 80% of patients at 6 months [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. A prospective phase II study of the effects of Denosumab treatment on pain for GCT of the bone across all sites reported Denosumab to be effective in reducing pain in both resectable and unresectable GCT with rapid and clinically relevant improvement in symptoms in both groups [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIt is worth noting that Denosumab therapy does carry additional risks. Osteonecrosis of the jaw, hypocalcemia, hypophosphataemia and rebound \u0026ndash; associated vertebral fractures are among the most common adverse side effects reported following its use and patients need to be carefully monitored for this during treatment [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e][\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eLimitations\u003c/h3\u003e\n\u003cp\u003eOur study had several limitations. As a single centre study, the case series is small and therefore the statistical significance of the results is limited. A multi-centre trial is required to generate an adequately powered study. There was no control group and hence no baseline for determining the effectiveness of the study treatment, although such a control group may raise ethical issues in a study such as this. Furthermore, there were no long-term outcome measures in the study, such as disease-free survival, long term pain relief, as the requisite follow up for inclusion in the study was 6 months. Finally, the pain scoring system was subjective and not validated. Despite these limitations we believe the study results provide good evidence of the beneficial effect of neo \u0026ndash; adjuvant Denosumab in this setting which adds to the limited current available literature on the topic.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study attempted to answer the question of whether denosumab is an effective neo \u0026ndash; adjuvant treatment for GCT of the spine. Our results have shown that treatment significantly improves pain in the majority of patients, and effects pre\u0026ndash;operative reduction in tumour volume and new bone formation. Metabolic activity is also significantly reduced. These factors facilitate en bloc resection of the tumour and reduces the likelihood of intra - operative morbidity. We would therefore recommend routine use when W-B-B \u0026ndash; based criteria are fulfilled for en \u0026ndash; bloc excision. Assuming that margins are disease \u0026ndash; free following surgery, we advocate cessation of treatment post \u0026ndash; operatively.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u0026nbsp;\u003c/strong\u003eour institutional review board approved this study\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u0026nbsp;\u003c/strong\u003eAll data generated or analysed during this study are included in this published article\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003eThe authors declare they have no competing interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003enot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors contributions:\u0026nbsp;\u003c/strong\u003eNBC collected and analysed data and wrote manuscript. CD analysed data and contributed to manuscript editing. GM collected and analysed data and contributed to manuscript editing. JJR collected and analysed data, contributed to manuscript editing, and was senior author. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u0026nbsp;\u003c/strong\u003enot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLuther N, Bilsky M, Hartl R; Giant Cell Tumour of the Spine; Neurosurg Clinc N Am 19 (2008) 49\u0026ndash;55\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLuksanapruksa et al; Management of spinal giant cell tumours; Spine J 2016 Feb;16(2):259\u0026ndash;69\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRaskin K et al; Giant Cell Tumour of the Bone; J Am Acad Orthop Surg 2013; 21: 118\u0026ndash;126\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHarrop et al; Aggressive \u0026lsquo;Benign\u0026rsquo; primary spine neoplasms; Spine, 34 (22S); S39 \u0026ndash; S47, 2009\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCharest \u0026ndash; Morin et al; En bloc resection versus intralesional surgery in the treatment of giant cell tumour of the spine. Spine 42(18):1383\u0026ndash;1390\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBoriani et al; Denosumab in the treatment of giant cell tumour of the spine. Preliminary report, review of the literature and protocol proposal; Eur Spine J 2020 Feb; 29(2):257\u0026ndash;271\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLeggon RE, Zlotecki R, Reith J, et al. Giant cell tumor of the pelvis and sacrum: 17 cases and analysis of the literature. Clin Orthop Relat Res 2004; 423:196\u0026ndash;207\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLin et al; Long term follow up of patients with giant cell tumour of the sacrum treated with selective arterial embolization; Cancer 2002;95:1317\u0026ndash;25\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBranstetter DG, Nelson SD, Manivel JC, et al. Denosumab Induces Tumor Reduction and Bone Formation in Patients with Giant-Cell Tumor of Bone. Clinical Cancer Research. 2012;18(16):4415\u0026ndash;4424. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1158/1078-0432.CCR-12-0578\u003c/span\u003e\u003cspan address=\"10.1158/1078-0432.CCR-12-0578\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThomas D, Henshaw R, Skubitz K, Chawla S, Staddon A, Blay JY, et al. Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study. Lancet Oncol 2010;11:275\u0026ndash;80\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLewin J, Thomas D. Denosumab: a new treatment option for giant cell tumor of bone. Drugs Today 2013;49:693\u0026ndash;700.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGoldschlager T, Dea N, Boyd M, et al. Giant cell tumors of the spine: has denosumab changed the treatment paradigm? J Neurosurg Spine. 2017;91:526\u0026ndash;533.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen et al; Therapeutic benefits of neo- adjuvant and post \u0026ndash; operative Denosumab on sacral giant cell tumour: a retrospective cohort study of 30 cases; JBUONMar-Apr 2018;23(2):453\u0026ndash;459\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBilsky M et al; Reliability analysis of the epidural spinal cord compression scale J Neurosurg spine. 2010 Sep; 13(3):324\u0026ndash;8\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBoriani, S et al., Spine, 22, 1036\u0026ndash;1044, 1997\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEnneking WF. A system of staging musculoskeletal neoplasms. Clin Orthop Relat Res. 1986; (204):9\u0026ndash;24\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGibiansky L et al; Population pharmacokinetics analysis of denosumab in patients with bone metastases from solid tumours; Clin Pharmacokinet 2012 Apr 1;51(4):247 \u0026ndash; 60\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e18.: Engellau et al; Assessmenrt of Denosumab treatment effects and imagine response in patients with giant cell tumour of bone. World J Surg Oncol. 2018\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e19.: Boye K et al; Denosumab in patients with giant cell tumour of bone in Norway: results from a nationwide cohort; Acta Oncol. 2017.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChawla S, Henshaw R, Seeger L, Choy E, Blay JY, Ferrari S, Kroep J, Grimer R, Reichardt P, Rutkowski P et al (2013) Safety and efficacy of denosumab for adults and skeletally mature adoles- cents with giant cell tumour of bone: interim analysis of an open- label, parallel-group, phase 2 study. Lancet Oncol 14:901\u0026ndash;908\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eErrani C, Tsukamoto S, Mavrogenis A. How safe and effective is denosumab for bone giant cell tumour? Int Orthop. 2017. Nov; 41(11): 2397\u0026ndash;2400;\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTraub et al. Efficacy of Denosumab in joint preservation for patients with giant cell tumour of the bone. Eur J Cancer. 2016 May. 59: 1\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMartin-Broto J et al. Effects of Denosumab on pain and analgesic use in giant cell tumour of bone: interim results from a phase II study. Acta Oncol. 2014 Sep; 53(9): 1173\u0026ndash;9\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eManzaneque A, Chaguaceda C, Mensa M, Bastida C, Creus-Bar\u0026oacute; N (2017) Use and safety of denosumab in cancer patients. Int J Clin Pharm 39(3):522\u0026ndash;526.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePopp AW, Zysset PK, Lippuner K (2016) Rebound-associated ver- tebral fractures after discontinuation of denosumab\u0026mdash;from clinic and biomechanics. Osteoporos Int 27:1917\u0026ndash;1921\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Giant cell tumour, denosumab, neo – adjuvant, en bloc excision, pain","lastPublishedDoi":"10.21203/rs.3.rs-2405951/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2405951/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe current recommended treatment for Giant Cell Tumour of the spine is en bloc excision. Denosumab is a monoclonal RANKL inhibitor that shows promising results when used as a neo \u0026ndash; adjuvant treatment. The purpose of this study was to assess the effect of Denosumab on tumour characteristics and symptom relief.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003e We performed a retrospective review of 12 patients treated with denosumab as neo adjuvant and stand - alone treatment. Tumour volume and PET SUV capitation measurements were taken before and after treatment and patients were interviewed for subjective pain responses. Clinical response was determined by reduction in tumour volume, PET SUV capitation, the Boriani calcification response classification, improvement in the Bilsky epidural grading and WBB layers and improvement in pain.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eFollowing treatment 75% of patients were pain free with 58% noting improvement within 48 hours. Mean relative volumetric reduction in tumour volume was 42%. All pathology specimens confirmed elimination of giant cells. Improvement in Bilsky epidural disease grading occurred in 7/12 cases. Median baseline SUVmax was 14.7 and post treatment was 3.3. Sixty - seven percent of patients demonstrated intralesional bone formation following treatment. At one year follow-up, there were no cases of local disease recurrence, malignant transformation or metastases.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThis study demonstrates neo-adjuvant denosumab can facilitate en bloc resection by reducing the tumour burden around critical adjacent neurovascular structures, reducing the risk morbidity and improving preoperative pain. We recommend routine use when W-B-B \u0026ndash; based criteria are fulfilled for en \u0026ndash; bloc excision.\u003c/p\u003e","manuscriptTitle":"The Use of Neo – Adjuvant Denosumab in Treatment of Giant Cell Tumours of the Spine","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-12-29 17:08:53","doi":"10.21203/rs.3.rs-2405951/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"db0e7898-5944-404e-be80-96069198c5fc","owner":[],"postedDate":"December 29th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-01-02T07:59:19+00:00","versionOfRecord":[],"versionCreatedAt":"2022-12-29 17:08:53","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2405951","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2405951","identity":"rs-2405951","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}