Bone modifying agents and skeletal related events in patients with metastatic non-small cell lung cancer treated with immune checkpoint inhibitors.

e18593 Background: Bone metastases and skeletal related events (SREs) are a common cause of morbidity among patients with metastatic non-small cell lung cancer (mNSCLC). SREs include pathologic bone fractures, spinal cord compression, orthopedic surgery/stabilization, and palliative radiation to bone. Bone modifying agents (BMA) such as bisphosphonates and RANK ligand inhibitors are often used for mNSCLC patients with bone metastases to reduce the incidence of SRE. Data on the associations between BMA use and overall survival (OS) and the development of SRE among patients with mNSCLC treated with immune checkpoint inhibitors (ICI) is limited. Methods: We conducted a retrospective study of patients with mNSCLC treated with first line pembrolizumab or pembrolizumab plus chemotherapy at The Ohio State University from 2017-2020. The associations between SRE and categorical variables were studied using Fisher’s exact test and with continuous variables using the Kruskal-Wallis test. The association between BMA and risk of osseous progression was studied using Fisher’s exact test. The association between BMA and OS was examined using a Cox proportional hazard model. Median OS was estimated using the Kaplan-Meier method with 95% CI. OS was calculated from date of ICI initiation to death from any cause or last follow up. Results: We identified a cohort of 228 patients: 107 (47%) treated with pembrolizumab and 121 (53%) treated with pembrolizumab plus chemotherapy; 48 (21%) had squamous histology and 179 (79%) had nonsquamous histology (1 had NSCLC histology not specified); median age 62.6 years; median OS was 26.8 months (95% CI: 17.2 – 34.5 months). A total of 95/228 (42%) patients had bone metastases at time of ICI initiation; 45/95 (42%) had treatment with BMA and 50/95 (58%) were not treated with BMA. Among patients with bone metastases at time of ICI, 45 (42%) developed SRE after ICI initiation and BMA use was not associated with risk of SRE (p = 1). BMA use was not significantly associated with risk of osseous progression (p = 0.21). For patients with baseline bone metastases prior to ICI, the use of BMA was not associated with OS (p = 0.24); the type of BMA used (bisphosphonate vs RANK ligand inhibitor) was also not associated with OS (p = 0.13). Conclusions: In patients with metastatic NSCLC treated with first line pembrolizumab alone or with chemotherapy, bone modifying agents were not associated with OS, decreased risk of osseous progression, or development of SRE in patients with baseline bone metastases prior to ICI initiation. The type of BMA used was also not associated with survival. Further studies evaluating the utility and impact of BMA use in this patient population are needed.

Symptomatic Rebound Hypercalcemia After Denosumab Discontinuation in a Pediatric Patient With Cherubism

Background: Pediatric bone diseases due to osteoclast overactivity have limited therapeutic options. Denosumab, a human monoclonal antibody against RANK-ligand, has been used in the treatment of these conditions despite limited pediatric safety data. Rebound hypercalcemia after denosumab cessation is a rare and potentially serious complication in children with an unpredictable course (1). We present the first report of a child with cherubism who experienced acute symptomatic hypercalcemia five months after denosumab cessation. Clinical Case: An 11 year old male presented to our emergency department (ED) with 2 weeks of nausea, vomiting, abdominal pain, and bilateral leg pain. He was diagnosed with cherubism at age 3 years with progressive painless bilateral jaw swelling, teeth crowding, and proptosis. His bilateral maxilla and left mandible were debulked between ages 5-8 years due to tumors causing dyspnea. The resected tumors showed RANK-ligand expression. Thus, he started a 1-year course of denosumab 80 mg monthly subcutaneous injections for additional lesions not amenable to surgery with marked clinical and radiographic improvement. He had mild hypocalcemia during denosumab therapy, for which he received cholecalciferol 2000 IU and calcium citrate total 1500 mg per day. Calcium citrate was stopped with corrected serum calcium (Ca) 10.1 mg/dL (8.8-10.8 mg/dL) three months prior to ED visit. His presentation to ED five months after denosumab revealed marked hypercalcemia (corrected Ca 13.9 mg/dL), iPTH 5.4 pg/mL (7.5-53.5 pg/mL), 25-OH vitamin D 19 ng/mL (30-100 ng/mL), and hypercalciuria (urine Ca/creatinine ratio 0.58 mg/mg, normal <0.2 mg/mg) concerning for rebound hypercalcemia post-denosumab therapy. He received IV hyperhydration, furosemide, calcitonin, and IV pamidronate 0.5 mg/kg. At discharge, corrected Ca was 8.7 mg/dL. One week later he developed acute nausea and vomiting. Laboratory tests again showed hypercalcemia (Ca 13.3 mg/dL) and hypercalciuria. He received one dose of IV zoledronic acid at 0.025 mg/kg with resolution of hypercalcemia. He remains normocalcemic, normocalciuric, and asymptomatic two months after zoledronic acid treatment. Conclusion: This is the first case, to our knowledge, of a pediatric patient with cherubism with acute symptomatic hypercalcemia after denosumab treatment, reinforcing the need for frequent calcium monitoring months after cessation. Zoledronic acid is also shown to effectively treat rebound hypercalcemia after denosumab cessation. Larger studies are needed to further evaluate denosumab use and safety in pediatric bone diseases with osteoclast overactivity. Reference: (1)Upfill-Brown A, Bukata S, Bernthal NM, Felsenfeld AL, Nelson SD, Singh A, Wesseling-Perry K, Eilber FC, Federman NC. Use of Denosumab in Children With Osteoclast Bone Dysplasias: Report of Three Cases. JBMR Plus. 2019 Aug 22;3(10):e10210

Bone Resorption in Ameloblastoma and Its Underlying Mechanism

Ameloblastoma, a tumor located in the jaw, grows slowly but locally invasive. Ameloblastoma expands in the jaw based on a mechanism resorbing the surrounding bone. To date, the bone resorption mechanisms of ameloblastoma are associated with the expression of receptor activator of nuclear factor (NF)-κB (RANK) ligand (RANKL), matrix metalloproteinases (MMPs), and tumor necrosis factor (TNF)-α. RANKL plays an important role in generating osteoclastogenesis. MMPs degrade the extracellular matrix. TNF-α can induce the formation of osteoclast and modulate the MMPs. In this review the bone resorption mechanism of ameloblastoma as well its signaling pathway will be disclosed.Keywords: Ameloblastoma, RANKL, MMPs, TNF-α.

The Role of Bone in Muscle Wasting

This review describes the role of bone resorption in muscle atrophy as well as in muscle protein anabolism. Both catabolic and anabolic pathways involve components of the proinflammatory cytokine families and release of factors stored in bone during resorption. The juxtaposition of the catabolic and anabolic resorption-dependent pathways raises new questions about control of release of factors from bone, quantity of release in a variety of conditions, and relation of factors released from bone. The catabolic responses involve release of calcium from bone into the circulation resulting in increased inflammatory response in intensity and/or duration. The release of transforming growth factor beta (TGF-β) from bone suppresses phosphorylation of the AKT/mTOR pathway and stimulates ubiquitin-mediated breakdown of muscle protein. In contrast, muscle IL-6 production is stimulated by undercarboxylated osteocalcin, which signals osteoblasts to produce more RANK ligand, stimulating resorptive release of undercarboxylated osteocalcin, which in turn stimulates muscle fiber nutrient uptake and an increase in muscle mass.

AB1017 ANTI RANK LIGAND IN ACUTE CHARCOT NEURO-OSTEOATHROPATHY OF THE FOOT: A PROMISING TREATMENT

Background:Acute Charcot neuroarthropathy (CN) of the foot is a rare and severe complication of peripheral neuropathy leading to joint destruction. Usual treatment rely on standard pressure offloading and no pharmacological treatment is available. Inflammation and increased osteoclastic activity via receptor activator of nuclear factor (RANK) ligand are major features of acute CN.Objectives:To assess clinical, metabolic and radiographic effect of denosumab, a fully human monoclonal antibody against RANK ligand, in acute CN.Methods:In this open study, we included all consecutive patients with acute CN treated with denosumab 60 mg in our mixed rheumatology/diabetes clinic dedicated to diabetic foot. Diagnosis of acute CN was based on clinical presentation and supported by biology, radiography, magnetic resonance imaging (MRI). Baseline and follow-up assessment included clinical examination and emission tomography–computed tomography (PET-CT).Results:Seven patients with acute CN were treated with denosumab between 2017 and 2019 (age from 43 to 70 years). Five were diabetic. All patients received denosumab, because of failure of standard pressure offloading, with evolving joint destruction of midfoot. CN evolves since a median of 6 months (2 to 20) at denosumab initiation. All patients clinically improved after denosumab injection (table). After a mean follow-up of 16 months, only 1/7 patients had a new flare. In the 4 patients with available follow-up X-ray, structural damage remained stable. In all 3 patients with available PET-CT evolution, the maximum standardized uptake lean value (SUL max) decreased.Table 1.Baseline characteristics and follow up treatmentThree patients were retreated, with a mean interval of 6 months: One patients because of persistent clinical and biological inflammation (CRP 17 mg/L), one because of relapse due to intensive walking, and one due to an associated osteoporosis.No adverse event and hypocalcemia was observed.Conclusion:One to three injection of denosumab 60 mg was efficient in preventing flare and further bone destruction in a 16 months medium follow up. These results justify the conduction of a randomized control study to assess the efficacy of denosumab as the first-line pharmacological therapy in acute CN.References:[1]Molines L and al. Charcot’s foot: Newest findings on its pathophysiology, diagnosis and treatment. Diabetes Metab. Sept 2010;36(4):251-5.[2]Mabilleau G, and al. Increased osteoclastic activity in acute Charcot’s osteoarthropathy: the role of receptor activator of nuclear factor-kappaB ligand. Diabetologia. juin 2008;51(6):1035-40.Disclosure of Interests:None declaredDisclosure of Interests:Sandrine Carvès: None declared, Julien Henry: None declared, Murielle BOURGEON GHITTORI: None declared, Rakiba Belkhir: None declared, Gaetane Nocturne: None declared, Florent Besson: None declared, Guillaume Cluzel: None declared, Maud Creze: None declared, Raphaèle Seror Consultant of: BMS UCB Pfizer Roche, Xavier Mariette Consultant of: BMS, Gilead, Medimmune, Novartis, Pfizer, Servier, UCB

SAT0474 WHAT DETERMINES THE EFFECT OF THERAPY WITH DENOSUMAB ON BONE IN WOMEN WITH RHEUMATOID ARTHRITIS AND OSTEOPOROSIS

Background:RANK-ligand is essential for osteoclast development, activation, and survival and it is a key mediator of increased osteoclast activity in rheumatoid arthritis (RA). Denosumab is a monoclonal antibody that binds RANK-ligand.Objectives:The aim of this study was to evaluate the effects of denosumab on bone mineral density (BMD) and to define a contribution of factors: anamnesis, clinical/laboratory markers, glucocorticoids (GC) intake, etc. on the response to therapy with denosumab in women with RA and osteoporosis (OP).Methods:66 postmenopausal women (mean age 59,6±7,4) with RA (mean duration 17,7±10,4 years) and OP received s/c denosumab 60 mg every 6 months pro 12 months. RF-positive were 72%, ACCP – 74% of patients. 34 (49%) patients continued GC. At baseline and after 12 months it was carried out the dual energy x-ray absorptiometry at 3 sites: lumbar spine (L1-L4), hip neck (HN) and distal forearm (DF) and x-ray of hands and feet (Sharp/van der Heijde (SVH) score). The Statistica 6.0 was used.Results:After therapy it was noted the increase (р < 0,05) of BMD in L1-L4 and HN, a tendency to increase (р =0,0529) in DF. Mean BMD (L1-L4) before\after the treatment was 0,821 ± 0,104 g/cm2vs 0,864 ± 0,110 g/cm2, at HN was 0,625 ± 0,089 g/сm2vs 0,639 ± 0,088 g/сm2, at DF was 0,498 ± 0,090 g/сm2vs 0,503 ± 0,089 g/сm2. The mean change of BMD (%) after 12 months at L1-L4 was +4,6%, at HN +2,8%, at DF +0,7%. Positive response (increase or stabilization of BMD) was noted in 89% patients at L1-L4, 67% - at HN and 60% - at DF. Analysis of influence of various factors (statistically significant) on the response to therapy is presented in the Table.Table.Influence of various factors on the response to therapy with denosumab after 12 months of treatment (n=66)DXA sitePositive response on therapy is associated withNegative response on therapy is associated withL1-L4–- GC intake (> 3 months in anamnesis) (р = 0,034);- the beginning of GC intake after menopause (р = 0,023)Hip neck- higher concentration of the RF (initially and in dynamics) (р < 0,05);- the beginning of menopause later than RA onset (р = 0,024)- GC intake (> 3 months in anamnesis) (р = 0,024)Forearm (distal 1/3)- RF-positivity (р = 0,02)- back correlates with increase in erosion score and total SVH score: r = –0,360 (р < 0,05)Conclusion:After 12 months of therapy with denosumab in postmenopausal women with RA and OP it was shown the significant increase of BMD in L1-L4 and HN, a tendency to increase in DF. The mean change of BMD (%) after 12 months was +4,6% at L1-L4, at HN +2,8%, at DF +0,7%. Positive response on denosumab (BMD) was noted in 89% patients at L1-L4, 67% - at HN and 60% - at DF. Analysis of influence of factors on the response to therapy showed that positive response on therapy in NH and DF was associated with RF-positivity. The distinct contribution to the negative response in L1-L4 and HN was associated with GC intake (previous intake more than 3 months in the anamnesis) and purpose of the GC after menopause onset. Also, negative response in DF back correlated with increase in erosion score and total SVH score.Disclosure of Interests:None declared