Denosumab: targeting the RANKL pathway to treat rheumatoid arthritis

References

• Lacey DL, Timms E, Tan HL, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. 1998;93(2):165–176.
   PubMed Web of Science ®Google Scholar
• Lacey DL, Tan HL, Lu J, et al. Osteoprotegerin ligand modulates murine osteoclast survival in vitro and in vivo. Am J Pathol. 2000;157(2):435–448. DOI:10.1016/S0002-9440(10)64556-7
   PubMed Web of Science ®Google Scholar
• Papapoulos S, Lippuner K, Roux C, et al., The effect of 8 or 5 years of denosumab treatment in postmenopausal women with osteoporosis: results from the FREEDOM Extension study. Osteoporos Int. 26(12): 2773–2783. 2015. DOI:10.1007/s00198-015-3234-7
   PubMed Web of Science ®Google Scholar
• Torring O. Effects of denosumab on bone density, mass and strength in women with postmenopausal osteoporosis. Ther Adv Musculoskelet Dis. 2015;7(3):88–102. DOI:10.1177/1759720X15579189.
   PubMed Web of Science ®Google Scholar
• Adami S, Libanati C, Boonen S, et al. Denosumab treatment in postmenopausal women with osteoporosis does not interfere with fracture-healing: results from the FREEDOM trial. J Bone Joint Surg Am. 2012;94(23):2113–2119. DOI:10.2106/JBJS.K.00774
   PubMed Web of Science ®Google Scholar
• Takeuchi T, Tanaka Y, Ishiguro N, et al. Response to: ‘Denosumab, cortical bone and bone erosion in rheumatoid arthritis’ by Rossini. Ann Rheum Dis. 2016;75(10):e71. DOI:10.1136/annrheumdis-2016-210027
   Google Scholar
• Rossini M, Adami G, Viapiana O, et al. Denosumab, cortical bone and bone erosions in rheumatoid arthritis. Ann Rheum Dis. 2016;75(10):e70. DOI:10.1136/annrheumdis-2016-210022.
   Google Scholar
• Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756–765. DOI:10.1056/NEJMoa0809493
   PubMed Web of Science ®Google Scholar
• Diedhiou D, Cuny T, Sarr A, et al. Efficacy and safety of denosumab for the treatment of osteoporosis: a systematic review. Ann Endocrinol (Paris). 2015;76(6):650–657. DOI:10.1016/j.ando.2015.10.009.
   PubMed Web of Science ®Google Scholar
• Zebaze RM, Libanati C, McClung MR, et al. Denosumab reduces cortical porosity of the proximal femoral shaft in postmenopausal women with osteoporosis. J Bone Miner Res. 2016;31:1827–1834. DOI:10.1002/jbmr.v31.10.
   PubMed Web of Science ®Google Scholar
• Zhou Z, Chen C, Zhang J, et al. Safety of denosumab in postmenopausal women with osteoporosis or low bone mineral density: a meta-analysis. Int J Clin Exp Pathol. 2014;7(5):2113–2122.
   PubMed Web of Science ®Google Scholar
• Cleeland CS, Body JJ, Stopeck A, et al. Pain outcomes in patients with advanced breast cancer and bone metastases: results from a randomized, double-blind study of denosumab and zoledronic acid. Cancer. 2013;119(4):832–838. DOI:10.1002/cncr.27789
   PubMed Web of Science ®Google Scholar
• Martin M, Bell R, Bourgeois H, et al. Bone-related complications and quality of life in advanced breast cancer: results from a randomized phase III trial of denosumab versus zoledronic acid. Clin Cancer Res. 2012;18(17):4841–4849. DOI:10.1158/1078-0432.CCR-11-3310
   PubMed Web of Science ®Google Scholar
• Stopeck A. Denosumab findings in metastatic breast cancer. Clin Adv Hematol Oncol. 2010;8(3):159–160.
   PubMedGoogle Scholar
• Stopeck AT, Fizazi K, Body JJ, et al. Safety of long-term denosumab therapy: results from the open label extension phase of two phase 3 studies in patients with metastatic breast and prostate cancer. Support Care Cancer. 2016;24(1):447–455. DOI:10.1007/s00520-015-2904-5
   PubMed Web of Science ®Google Scholar
• Stopeck AT, Lipton A, Body JJ, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. 2010;28(35):5132–5139. DOI:10.1200/JCO.2010.29.7101
   PubMed Web of Science ®Google Scholar
• Wang X, Yang KH, Wanyan P, et al. Comparison of the efficacy and safety of denosumab versus bisphosphonates in breast cancer and bone metastases treatment: a meta-analysis of randomized controlled trials. Oncology Letters. 2014;7(6):1997–2002. DOI:10.3892/ol.2014.1982.
   PubMed Web of Science ®Google Scholar
• Hensvold AH, Joshua V, Li W, et al. Serum RANKL levels associate with anti- citrullinated protein antibodies in early untreated rheumatoid arthritis and are modulated following methotrexate. Arthritis Res Ther. 2015;17:239. DOI:10.1186/s13075-015-0760-9.
   PubMed Web of Science ®Google Scholar
• Li CH, Xu LL, Zhao JX, et al. CXCL16 upregulates RANKL expression in rheumatoid arthritis synovial fibroblasts through the JAK2/STAT3 and p38/MAPK signaling pathway. Inflamm Res. 2016;65(3):193–202. DOI:10.1007/s00011-015-0905-y
   PubMed Web of Science ®Google Scholar
• Hoyer-Kuhn H, Franklin J, Allo G, et al. Safety and efficacy of denosumab in children with osteogenesis imperfecta - a first prospective trial. J Musculoskelet Neuronal Interact. 2016;16(1):24–32.
   PubMed Web of Science ®Google Scholar
• Langdahl BL, Teglbjaerg CS, Ho PR, et al. A 24-month study evaluating the efficacy and safety of denosumab for the treatment of men with low bone mineral density: results from the ADAMO trial. J Clin Endocrinol Metab. 2015;100(4):1335–1342. DOI:10.1210/jc.2014-4079
   PubMed Web of Science ®Google Scholar
• Sharp T, Tsuji W, Ory P, et al. Denosumab prevents metacarpal shaft cortical bone loss in patients with erosive rheumatoid arthritis. Arthritis Care Res. 2010;62(4): 537–544. DOI:10.1002/acr.20172
   Web of Science ®Google Scholar
• Gatti D, Viapiana O, Fracassi E, et al. Sclerostin and DKK1 in postmenopausal osteoporosis treated with denosumab. J Bone Miner Res. 2012;27(11):2259–2263. DOI:10.1002/jbmr.1681
   PubMed Web of Science ®Google Scholar
• Brown JE, Coleman RE. Denosumab in patients with cancer-a surgical strike against the osteoclast. Nat Rev Clin Oncol. 2012;9(2):110–118. DOI:10.1038/nrclinonc.2011.197.
   PubMed Web of Science ®Google Scholar
• Brown-Glaberman U, Stopeck AT. Impact of denosumab on bone mass in cancer patients. Clin Pharmacol. 2013;5:117–129. DOI:10.2147/CPAA.S30330.
   PubMedGoogle Scholar
• Cohen SB, Dore RK, Lane NE, et al., Denosumab treatment effects on structural damage, bone mineral density, and bone turnover in rheumatoid arthritis: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, phase II clinical trial. Arthritis Rheum. 58(5): 1299–1309. 2008. DOI:10.1002/art.23417
   PubMed Web of Science ®Google Scholar
• Hasegawa T, Kaneko Y, Izumi K, et al. Efficacy of denosumab combined with bDMARDs on radiographic progression in rheumatoid arthritis. Joint Bone Spine. 2016. DOI:10.1016/j.jbspin.2016.05.010.
   PubMedGoogle Scholar
• Castellano D, Sepulveda JM, Garcia-Escobar I, et al. The role of RANK-ligand inhibition in cancer: the story of denosumab. Oncologist. 2011;16(2):136–145. DOI:10.1634/theoncologist.2010-0154.
   PubMed Web of Science ®Google Scholar
• Laskowski LK, Goldfarb DS, Howland MA, et al. A RANKL wrinkle: denosumab-induced hypocalcemia. J Med Toxicol. 2016;12:305–308. DOI:10.1007/s13181-016-0543-y
   PubMed Web of Science ®Google Scholar
• Yerram P, Kansagra S, Abdelghany O. Incidence of hypocalcemia in patients receiving denosumab for prevention of skeletal-related events in bone metastasis. J Oncol Pharm Pract. 2016. DOI:10.1177/1078155216628325.
   Google Scholar
• Okada N, Kawazoe K, Teraoka K, et al. Identification of the risk factors associated with hypocalcemia induced by denosumab. Biol Pharm Bull. 2013;36(10):1622–1626.
   PubMed Web of Science ®Google Scholar
• Body JJ, Bone HG, De Boer RH, et al. Hypocalcaemia in patients with metastatic bone disease treated with denosumab. Eur J Cancer. 2015;51(13):1812–1821. DOI:10.1016/j.ejca.2015.05.016
   PubMed Web of Science ®Google Scholar
• Prolia. (FDA) FaDA. 2010. Available from: http://www.fda.gov/safety/medwatch/safetyinformation/safety-relateddruglabelingchanges/ucm307218.htm
   Google Scholar
• XGEVA, (FDA) FaDA. 2013. Available from: http://www.fda.gov/safety/medwatch/safetyinformation/ucm303740.htm, http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm356528.htm
   Google Scholar
• De souza povoa RC, Marliere DA, Da silveira HM, et al. Denosumab-related osteonecrosis of the jaws: successful management with a conservative surgical approach. Spec Care Dentist. 2016;36(4):231–236. DOI:10.1111/scd.12168.
   PubMed Web of Science ®Google Scholar
• Kyrgidis A, Toulis KA. Denosumab-related osteonecrosis of the jaws. Osteoporos Int. 2011;22(1):369–370. DOI:10.1007/s00198-010-1177-6.
   PubMed Web of Science ®Google Scholar
• Malan J, Ettinger K, Naumann E, et al. The relationship of denosumab pharmacology and osteonecrosis of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;114(6):671–676. DOI:10.1016/j.oooo.2012.08.439.
   PubMed Web of Science ®Google Scholar
• O’Halloran M, Boyd NM, Smith A. Denosumab and osteonecrosis of the jaws - the pharmacology, pathogenesis and a report of two cases. Aust Dent J. 2014;59(4):516–519. DOI:10.1111/adj.12217.
   PubMed Web of Science ®Google Scholar
• Pichardo SE, Van merkesteyn JP. Evaluation of a surgical treatment of denosumab-related osteonecrosis of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol. 2016. DOI:10.1016/j.oooo.2016.03.008.
   PubMed Web of Science ®Google Scholar
• Sivolella S, Lumachi F, Stellini E, et al. Denosumab and anti-angiogenetic drug-related osteonecrosis of the jaw: an uncommon but potentially severe disease. Anticancer Res. 2013;33(5):1793–1797.
   PubMed Web of Science ®Google Scholar
• Matsushita Y, Hayashida S, Morishita K, et al. Denosumab-associated osteonecrosis of the jaw affects osteoclast formation and differentiation: pathological features of two cases. Mol Clin Oncol. 2016;4(2):191–194. DOI:10.3892/mco.2015.696
   PubMedGoogle Scholar
• Di Nisio C, Zizzari VL, Zara S, et al. RANK/RANKL/OPG signaling pathways in necrotic jaw bone from bisphosphonate-treated subjects. Eur J Histochem. 2015;59(1):2455. DOI:10.4081/ejh.2015.2455
   PubMed Web of Science ®Google Scholar
• Selga J, Nunez JH, Minguell J, et al. Simultaneous bilateral atypical femoral fracture in a patient receiving denosumab: case report and literature review. Osteoporos Int. 2016;27(2):827–832. DOI:10.1007/s00198-015-3355-z.
   PubMed Web of Science ®Google Scholar
• Edwards BJ, Sun M, West DP, et al. Incidence of atypical femur fractures in cancer patients: the MD Anderson cancer center experience. J Bone Miner Res. 2016;31(8):1569–1576. DOI:10.1002/jbmr.2818
   PubMed Web of Science ®Google Scholar
• Edwards BJ, Gradishar WJ, Smith ME, et al. Elevated incidence of fractures in women with invasive breast cancer. Osteoporos Int. 2016;27(2):499–507. DOI:10.1007/s00198-015-3246-3
   PubMed Web of Science ®Google Scholar
• Villiers J, Clark DW, Jeswani T, et al. An atraumatic femoral fracture in a patient with rheumatoid arthritis and osteoporosis treated with denosumab. Case Rep Rheumatol. 2013;2013:249872.
   PubMedGoogle Scholar
• Teixeira MZ. Antiresorptive drugs (bisphosphonates), atypical fractures and rebound effect: new evidence of similitude. Homeopathy. 2012;101(4):231–242. DOI:10.1016/j.homp.2012.07.001.
   PubMed Web of Science ®Google Scholar
• Popp AW, Zysset PK, Lippuner K. Rebound-associated vertebral fractures after discontinuation of denosumab-from clinic and biomechanics. Osteoporos Int. 2016;27(5):1917–1921. DOI:10.1007/s00198-015-3458-6.
   PubMed Web of Science ®Google Scholar
• Baron R, Ferrari S, Russell RG. Denosumab and bisphosphonates: different mechanisms of action and effects. Bone. 2011;48(4):677–692. DOI:10.1016/j.bone.2010.11.020.
   PubMed Web of Science ®Google Scholar
• Rodan G, Reszka A, Golub E, et al. Bone safety of long-term bisphosphonate treatment. Curr Med Res Opin. 2004;20(8):1291–1300. DOI:10.1185/030079904125004475.
   PubMed Web of Science ®Google Scholar
• Tonino RP, Meunier PJ, Emkey R, et al. Skeletal benefits of alendronate: 7-year treatment of postmenopausal osteoporotic women. Phase III Osteoporosis Treatment Study Group. J Clin Endocrinol Metab. 2000;85(9):3109–3115. DOI:10.1210/jcem.85.9.6777
   PubMed Web of Science ®Google Scholar
• Bone HG, Hosking D, Devogelaer JP, et al. Ten years’ experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med. 2004;350(12):1189–1199. DOI:10.1056/NEJMoa030897
   PubMed Web of Science ®Google Scholar
• Dore RK, Cohen SB, Lane NE, et al., Effects of denosumab on bone mineral density and bone turnover in patients with rheumatoid arthritis receiving concurrent glucocorticoids or bisphosphonates. Ann Rheum Dis. 69(5): 872–875. 2010. DOI:10.1136/ard.2009.112920
   PubMed Web of Science ®Google Scholar
• Kinoshita H, Miyakoshi N, Kashiwagura T, et al. Comparison of the efficacy of denosumab and bisphosphonates for treating secondary osteoporosis in patients with rheumatoid arthritis. Mod Rheumatol. 2016;1–5. DOI:10.1080/14397595.2016.1232776.
   Google Scholar
• Adami G, Orsolini G, Adami S, et al. Effects of TNF inhibitors on parathyroid hormone and Wnt signaling antagonists in rheumatoid arthritis. Calcif Tissue Int. 2016;99:360–364. DOI:10.1007/s00223-016-0161-3.
   PubMed Web of Science ®Google Scholar
• Rossini M, Gatti D, Adami S. Involvement of WNT/beta-catenin signaling in the treatment of osteoporosis. Calcif Tissue Int. 2013;93(2):121–132. DOI:10.1007/s00223-013-9749-z.
   PubMed Web of Science ®Google Scholar
• Street_Journal_Market_Report AW. [ Available from: http://www.fool.com/investing/general/2014/02/03/xgeva-and-prolia-setting-the-pace-for-amgen-inc.aspxhttp://investors.amgen.com/phoenix.zhtml?c=61656&p=irol-newsArticle&ID=1653300http://marketrealist.com/2016/07/xgeva-nplate-sensipar-key-growth-drivers-amgens-revenues-2q16/
   Google Scholar
• Takeuchi T, Tanaka Y, Ishiguro N, et al., Effect of denosumab on Japanese patients with rheumatoid arthritis: a dose-response study of AMG 162 (denosumab) in patients with Rheumatoid arthritis on methotrexate to Validate inhibitory effect on bone Erosion (DRIVE)-a 12-month, multicentre, randomised, double-blind, placebo-controlled, phase II clinical trial. Ann Rheum Dis. 75(6): 983–990. 2016. DOI:10.1136/annrheumdis-2015-208052
   PubMed Web of Science ®Google Scholar
• Hazlewood GS, Barnabe C, Tomlinson G, et al. Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease modifying antirheumatic drugs for rheumatoid arthritis: abridged Cochrane systematic review and network meta-analysis. Bmj. 2016;353:i1777.
   PubMed Web of Science ®Google Scholar
• Kostenuik PJ, Smith SY, Samadfam R, et al. Effects of denosumab, alendronate, or denosumab following alendronate on bone turnover, calcium homeostasis, bone mass and bone strength in ovariectomized cynomolgus monkeys. J Bone Miner Res. 2015;30(4):657–669. DOI:10.1002/jbmr.2401
   PubMed Web of Science ®Google Scholar
• Xue Y, Cohen JM, Wright NA, et al. Skin signs of rheumatoid arthritis and its therapy-induced cutaneous side effects. Am J Clin Dermatol. 2016;17(2):147–162. DOI:10.1007/s40257-015-0167-z.
   PubMed Web of Science ®Google Scholar
• Baum R, Gravallese EM. Bone as a target organ in rheumatic disease: impact on osteoclasts and osteoblasts. Clin Rev Allergy Immunol. 2016;51(1):1–15.
   Web of Science ®Google Scholar
• Rossini M, Viapiana O, Adami S, et al. In patients with rheumatoid arthritis, Dickkopf-1 serum levels are correlated with parathyroid hormone, bone erosions and bone mineral density. Clin Exp Rheumatol. 2015;33(1):77–83.
   PubMed Web of Science ®Google Scholar
• Schett G, Gravallese E. Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment. Nat Rev Rheumatol. 2012;8(11):656–664. DOI:10.1038/nrrheum.2012.153.
   PubMed Web of Science ®Google Scholar
• Edrees AF, Misra SN, Abdou NI. Anti-tumor necrosis factor (TNF) therapy in rheumatoid arthritis: correlation of TNF-alpha serum level with clinical response and benefit from changing dose or frequency of infliximab infusions. Clin Exp Rheumatol. 2005;23(4):469–474.
   PubMed Web of Science ®Google Scholar
• Manicourt DH, Triki R, Fukuda K, et al. Levels of circulating tumor necrosis factor alpha and interleukin-6 in patients with rheumatoid arthritis. Relationship to serum levels of hyaluronan and antigenic keratan sulfate. Arthritis Rheum. 1993;36(4):490–499.
   PubMed Web of Science ®Google Scholar
• Sakito S, Ueki Y, Eguchi K, et al. Serum cytokines in patients with rheumatoid arthritis. Correlation of interferon gamma and tumor necrosis factor alpha with the characteristics of peripheral blood mononuclear cells. Rheumatol Int. 1995;15(1):31–37.
   PubMed Web of Science ®Google Scholar
• Yen JH, Chen JR, Tsai WJ, et al. Correlation of tumor necrosis factor alpha levels with disease activity of rheumatoid arthritis. Zhonghua Min Guo Wei Sheng Wu Ji Mian Yi Xue Za Zhi. 1992;25(4):232–243.
   PubMedGoogle Scholar
• Yeo L, Lom H, Juarez M, et al. Expression of FcRL4 defines a pro-inflammatory, RANKL-producing B cell subset in rheumatoid arthritis. Ann Rheum Dis. 2015;74(5):928–935. DOI:10.1136/annrheumdis-2013-204116
   PubMed Web of Science ®Google Scholar
• Meednu N, Zhang H, Owen T, et al. Production of RANKL by memory b cells: a link between b cells and bone erosion in rheumatoid arthritis. Arthritis & Rheumatology. 2016;68(4):805–816. DOI:10.1002/art.39489
   PubMed Web of Science ®Google Scholar
• Huang JC, Sakata T, Pfleger LL, et al. PTH differentially regulates expression of RANKL and OPG. J Bone Miner Res. 2004;19(2):235–244. DOI:10.1359/JBMR.0301226
   PubMed Web of Science ®Google Scholar
• Moller Dohn U, Boonen A, Hetland ML, et al. Erosive progression is minimal, but erosion healing rare, in patients with rheumatoid arthritis treated with adalimumab. A 1 year investigator-initiated follow-up study using high-resolution computed tomography as the primary outcome measure. Ann Rheum Dis. 2009;68(10):1585–1590. DOI:10.1136/ard.2008.097048
   PubMed Web of Science ®Google Scholar
• Humphrey MB, Lanier LL, Nakamura MC. Role of ITAM-containing adapter proteins and their receptors in the immune system and bone. Immunol Rev. 2005;208:50–65. DOI:10.1111/j.0105-2896.2005.00325.x.
   PubMed Web of Science ®Google Scholar
• Negishi-Koga T, Takayanagi H. Ca2+-NFATc1 signaling is an essential axis of osteoclast differentiation. Immunol Rev. 2009;231(1):241–256. DOI:10.1111/j.1600-065X.2009.00821.x.
   PubMed Web of Science ®Google Scholar
• Nakashima T, Takayanagi H. Osteoimmunology: crosstalk between the immune and bone systems. J Clin Immunol. 2009;29(5):555–567. DOI:10.1007/s10875-009-9316-6.
   PubMed Web of Science ®Google Scholar
• Takayanagi H, Kim S, Koga T, et al. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell. 2002;3(6):889–901.
   PubMed Web of Science ®Google Scholar
• Chiu YH1, Mensah KA, Schwarz EM, et al. Regulation of human osteoclast development by dendritic cell-specific transmembrane protein (DC-STAMP). J Bone Miner Res. 2012 Jan;27(1):79–92. DOI:10.1002/jbmr.531
   PubMed Web of Science ®Google Scholar
• Kanzaki H, Shinohara F, Kanako I, et al. Molecular regulatory mechanisms of osteoclastogenesis through cytoprotective enzymes. Redox Biol. 2016;8:186–191. DOI:10.1016/j.redox.2016.01.006.
   PubMed Web of Science ®Google Scholar
• Humphrey MB, Daws MR, Spusta SC, et al. TREM2, a DAP12-associated receptor, regulates osteoclast differentiation and function. J Bone Miner Res. 2006;21(2):237–245. DOI:10.1359/JBMR.051016
   PubMed Web of Science ®Google Scholar
• Nimmerjahn F, Ravetch JV. Fc-receptors as regulators of immunity. Adv Immunol. 2007;96:179–204. DOI:10.1016/S0065-2776(07)96005-8.
   PubMed Web of Science ®Google Scholar
• Luo J, Yang Z, Ma Y, et al., LGR4 is a receptor for RANKL and negatively regulates osteoclast differentiation and bone resorption. Nat Med. 22(5): 539–546. 2016. DOI:10.1038/nm.4076
   PubMed Web of Science ®Google Scholar
• Zaidi M, Iqbal J. Closing the loop on the bone-resorbing osteoclast. Nat Med. 2016;22(5):460–461. DOI:10.1038/nm.4104.
   PubMed Web of Science ®Google Scholar
• Bengtsson AK, Ryan EJ. Immune function of the decoy receptor osteoprotegerin. Crit Rev Immunol. 2002;22(3):201–215.
   PubMed Web of Science ®Google Scholar
• Kelesidis T, Currier JS, Yang OO, et al. Role of RANKL-RANK/osteoprotegerin pathway in cardiovascular and bone disease associated with HIV infection. AIDS Rev. 2014;16(3):123–133.
   PubMed Web of Science ®Google Scholar
• Kohli SS, Kohli VS. Role of RANKL-RANK/osteoprotegerin molecular complex in bone remodeling and its immunopathologic implications. Indian J Endocrinol Metab. 2011;15(3):175–181. DOI:10.4103/2230-8210.83401.
   PubMedGoogle Scholar
• Walsh MC, Choi Y. Biology of the RANKL-RANK-OPG system in immunity, bone, and beyond. Front Immunol. 2014;5:511. DOI:10.3389/fimmu.2014.00511.
   PubMed Web of Science ®Google Scholar
• Vanessa Nicolin DDI, Roberto V. Osteoimmunology represents a link between skeletal and immune system. Italian J Anat Embryol. 2016;121(1):37–42.
   Google Scholar
• Wong BR, Josien R, Lee SY, et al. TRANCE (tumor necrosis factor [TNF]-related activation-induced cytokine), a new TNF family member predominantly expressed in T cells, is a dendritic cell-specific survival factor. J Exp Med. 1997;186(12):2075–2080.
   PubMed Web of Science ®Google Scholar
• Kikuta J, Wada Y, Kowada T, et al. Dynamic visualization of RANKL and Th17-mediated osteoclast function. J Clin Invest. 2013;123(2):866–873. DOI:10.1172/JCI65054
   PubMed Web of Science ®Google Scholar
• Komatsu N, Okamoto K, Sawa S, et al. Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat Med. 2014;20(1):62–68. DOI:10.1038/nm.3432
   PubMed Web of Science ®Google Scholar
• Onal M, Xiong J, Chen X, et al. Receptor activator of nuclear factor kappaB ligand (RANKL) protein expression by B lymphocytes contributes to ovariectomy-induced bone loss. J Biol Chem. 2012;287(35):29851–29860. DOI:10.1074/jbc.M112.377945
   PubMed Web of Science ®Google Scholar
• Green EA, Choi Y, Flavell RA. Pancreatic lymph node-derived CD4(+)CD25(+) Treg cells: highly potent regulators of diabetes that require TRANCE-RANK signals. Immunity. 2002;16(2):183–191.
   PubMed Web of Science ®Google Scholar
• Totsuka T, Kanai T, Nemoto Y, et al. RANK-RANKL signaling pathway is critically involved in the function of CD4+CD25+ regulatory T cells in chronic colitis. J Immunol. 2009;182(10):6079–6087. DOI:10.4049/jimmunol.0711823
   PubMed Web of Science ®Google Scholar
• Loser K, Mehling A, Loeser S, et al. Epidermal RANKL controls regulatory T-cell numbers via activation of dendritic cells. Nat Med. 2006;12(12):1372–1379. DOI:10.1038/nm1518
   PubMed Web of Science ®Google Scholar
• Kong YY, Feige U, Sarosi I, et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature. 1999;402(6759):304–309. DOI:10.1038/46303
   PubMed Web of Science ®Google Scholar
• Pettit AR, Ji H, Von Stechow D, et al. TRANCE/RANKL knockout mice are protected from bone erosion in a serum transfer model of arthritis. Am J Pathol. 2001;159(5):1689–1699. DOI:10.1016/S0002-9440(10)63016-7
   PubMed Web of Science ®Google Scholar
• Boyce BF, Xing L. Biology of RANK, RANKL, and osteoprotegerin. Arthritis Res Ther. 2007;9(Suppl 1):S1. DOI:10.1186/ar2172.
   PubMed Web of Science ®Google Scholar
• Wang XF, Zhang YK, Yu ZS, et al. The role of the serum RANKL/OPG ratio in the healing of intertrochanteric fractures in elderly patients. Mol Med Rep. 2013;7(4):1169–1172. DOI:10.3892/mmr.2013.1335.
   PubMed Web of Science ®Google Scholar
• Wasilewska A, Rybi-Szuminska A, Zoch-Zwierz W. Serum RANKL, osteoprotegerin (OPG), and RANKL/OPG ratio in nephrotic children. Pediatr Nephrol. 2010;25(10):2067–2075. DOI:10.1007/s00467-010-1583-1.
   PubMed Web of Science ®Google Scholar
• Dougall WC, Glaccum M, Charrier K, et al. RANK is essential for osteoclast and lymph node development. Genes Dev. 1999;13(18):2412–2424.
   PubMed Web of Science ®Google Scholar
• Bachmann MF, Wong BR, Josien R, et al. TRANCE, a tumor necrosis factor family member critical for CD40 ligand-independent T helper cell activation. J Exp Med. 1999;189(7):1025–1031.
   PubMed Web of Science ®Google Scholar
• Ashcroft AJ, Cruickshank SM, Croucher PI, et al. Colonic dendritic cells, intestinal inflammation, and T cell-mediated bone destruction are modulated by recombinant osteoprotegerin. Immunity. 2003;19(6):849–861.
   PubMed Web of Science ®Google Scholar
• Bone HG, Bolognese MA, Yuen CK, et al. Effects of denosumab on bone mineral density and bone turnover in postmenopausal women. J Clin Endocrinol Metab. 2008;93(6):2149–2157. DOI:10.1210/jc.2007-2814
   PubMed Web of Science ®Google Scholar
• Baud’huin M, Lamoureux F, Duplomb L, et al. RANKL, RANK, osteoprotegerin: key partners of osteoimmunology and vascular diseases. Cellular and Molecular Life Sciences: CMLS. 2007;64(18):2334–2350. DOI:10.1007/s00018-007-7104-0.
   PubMed Web of Science ®Google Scholar
• Kiechl S, Werner P, Knoflach M, et al. The osteoprotegerin/RANK/RANKL system: a bone key to vascular disease. Expert Rev Cardiovasc Ther. 2006;4(6):801–811. DOI:10.1586/14779072.4.6.801.
   PubMedGoogle Scholar
• Rossini M, Viapiana O, Adami S, et al. Effects of denosumab on peripheral lymphocyte subpopulations. Endocrine. 2015;53(3):857–859. DOI:10.1007/s12020-015-0723-6.
   Web of Science ®Google Scholar
• Panizo S, Cardus A, Encinas M, et al. RANKL increases vascular smooth muscle cell calcification through a RANK-BMP4-dependent pathway. Circulation Research. 2009;104(9):1041–1048. DOI:10.1161/CIRCRESAHA.108.189001
   PubMed Web of Science ®Google Scholar
• Helas S, Goettsch C, Schoppet M, et al. Inhibition of receptor activator of NF-kappaB ligand by denosumab attenuates vascular calcium deposition in mice. Am J Pathol. 2009;175(2):473–478. DOI:10.2353/ajpath.2009.080957
   PubMed Web of Science ®Google Scholar
• Iolascon G, Napolano R, Gioia M, et al. The contribution of cortical and trabecular tissues to bone strength: insights from denosumab studies. Clin Cases Miner Bone Metab. 2013;10(1):47–51. DOI:10.11138/ccmbm/2013.10.1.047.
   PubMedGoogle Scholar
• Ostertag A, Cohen-Solal M, Audran M, et al. Vertebral fractures are associated with increased cortical porosity in iliac crest bone biopsy of men with idiopathic osteoporosis. Bone. 2009;44(3):413–417. DOI:10.1016/j.bone.2008.11.004
   PubMed Web of Science ®Google Scholar
• Kleyer A, Finzel S, Rech J, et al. Bone loss before the clinical onset of rheumatoid arthritis in subjects with anticitrullinated protein antibodies. Ann Rheum Dis. 2014;73(5):854–860. DOI:10.1136/annrheumdis-2012-202958
   PubMed Web of Science ®Google Scholar
• Yue J, Griffith JF, Xiao F, et al. Repair of bone erosion in rheumatoid arthritis by denosumab: a high-resolution peripheral quantitative computed tomography study. Arthritis Care Res (Hoboken). 2016. DOI:10.1002/acr.23133
   PubMedGoogle Scholar
• Deodhar A, Dore RK, Mandel D, et al., Denosumab-mediated increase in hand bone mineral density associated with decreased progression of bone erosion in rheumatoid arthritis patients. Arthritis Care Res (Hoboken). 62(4): 569–574. 2010. DOI:10.1002/acr.20004
   PubMed Web of Science ®Google Scholar
• Dore RK. The RANKL pathway and denosumab. Rheum Dis Clin North Am. 2011;37(3):433-52, vi-vii. DOI:10.1016/j.rdc.2011.07.004.
   PubMed Web of Science ®Google Scholar
• Takeuchi T, Tanaka Y, Ishiguro N, et al. Effect of denosumab on Japanese patients with rheumatoid arthritis: a dose-response study of AMG 162 (Denosumab) in patients with RheumatoId arthritis on methotrexate to Validate inhibitory effect on bone Erosion (DRIVE)-a 12-month, multicentre, randomised, double-blind, placebo-controlled, phase II clinical trial. Ann Rheum Dis. 2016;75(6):983–990. DOI:10.1136/annrheumdis-2015-208052.
   Web of Science ®Google Scholar
• Curtis JR, Xie F, Yun H, et al. Risk of hospitalized infection among rheumatoid arthritis patients concurrently treated with a biologic agent and denosumab. Arthritis Rheumatol. 2015;67(6):1456–1464. DOI:10.1002/art.39075
   PubMed Web of Science ®Google Scholar
• Boers M, Ac V, van der Linden S. Combination therapy in early rheumatoid arthritis: the COBRA study. Ned Tijdschr Geneeskd. 1997;141(50):2428–2432.
   PubMedGoogle Scholar
• Bathon JM, Martin RW, Fleischmann RM, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med. 2000;343(22):1586–1593. DOI:10.1056/NEJM200011303432201
   PubMed Web of Science ®Google Scholar
• Anandarajah A, Thiele R, Giampoli E, et al. Patients with rheumatoid arthritis in clinical remission manifest persistent joint inflammation on histology and imaging studies. J Rheumatol. 2014;41(11):2153–2160. DOI:10.3899/jrheum.140411
   PubMed Web of Science ®Google Scholar
• Brown AK, Quinn MA, Karim Z, et al. Presence of significant synovitis in rheumatoid arthritis patients with disease-modifying antirheumatic drug-induced clinical remission: evidence from an imaging study may explain structural progression. Arthritis Rheum. 2006;54(12):3761–3773. DOI:10.1002/art.22190
   PubMed Web of Science ®Google Scholar
• Schett G, Emery P, Tanaka Y, et al. Tapering biologic and conventional DMARD therapy in rheumatoid arthritis: current evidence and future directions. Ann Rheum Dis. 2016;75(8):1428–1437.
   PubMed Web of Science ®Google Scholar