{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T05:25:32Z","timestamp":1788413132917,"version":"build-2803163510"},"reference-count":24,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2024,9,30]],"date-time":"2024-09-30T00:00:00Z","timestamp":1727654400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,9,30]],"date-time":"2024-09-30T00:00:00Z","timestamp":1727654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Paget's Association"},{"DOI":"10.13039\/100010663","name":"H2020 European Research Council","doi-asserted-by":"publisher","award":["787270"],"award-info":[{"award-number":["787270"]}],"id":[{"id":"10.13039\/100010663","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Calcif Tissue Int"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Paget\u2019s disease of bone (PDB) is characterised by increased and disorganised bone remodelling leading to various complications, such as bone deformity, deafness, secondary osteoarthritis, and pathological fracture. Pain is the most common presenting symptom of PDB, but it is unclear to what extent this is due to increased metabolic activity of the disease, complications, or unrelated causes. We conducted a cross-sectional study of 168 people with PDB attending secondary care referral centres in the UK. We documented the presence of musculoskeletal pain and sought to determine its underlying causes. Musculoskeletal pain was reported by 122\/168 (72.6%) individuals. The most common cause was osteoarthritis of joints distant from an affected PDB site in 54 (44.3%), followed by metabolically active PDB in 18 (14.7%); bone deformity in 14 (11.4%); osteoarthritis of a joint neighbouring an affected site in 11 (9.0%), neuropathic pain in 10 (8.2%), and various other causes in the remainder. Pain was more common in women (<jats:italic>p<\/jats:italic>&lt;0.019) and in older individuals (<jats:italic>p<\/jats:italic>&lt;0.001). Circulating concentrations of macrophage colony-stimulating factor (M-CSF) were significantly higher in those with pain (<jats:italic>p<\/jats:italic> = 0.008), but there was no difference between groups of patients with and without pain in concentrations of interleukin-6 (IL-6) or biochemical markers of bone turnover. Pain is a common symptom in PDB but is most often due to osteoarthritis at an unaffected site. The study illustrates the importance of fully evaluating people with PDB to determine the underlying cause of pain so that management can be tailored appropriately.<\/jats:p>","DOI":"10.1007\/s00223-024-01279-0","type":"journal-article","created":{"date-parts":[[2024,9,30]],"date-time":"2024-09-30T19:02:35Z","timestamp":1727722955000},"page":"533-541","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Causes of Musculoskeletal Pain in Paget\u2019s Disease of Bone"],"prefix":"10.1007","volume":"115","author":[{"given":"Kathryn","family":"Berg","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dervil","family":"Dockrell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lesley","family":"Colvin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William D","family":"Fraser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan CY","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terry","family":"Aspray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine","family":"Dennison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hrushikesh","family":"Divyateja","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nazim","family":"Ghouri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Hanison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Keen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene","family":"McCloskey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terence W","family":"O\u2019Neill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faizanur","family":"Rahman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mashood","family":"Siddiqi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Tuck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"Turton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2804-7586","authenticated-orcid":false,"given":"Stuart H","family":"Ralston","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,9,30]]},"reference":[{"key":"1279_CR1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keab232","author":"MJ Cook","year":"2021","unstructured":"Cook MJ, Pye SR, Lunt M, Dixon WG, Ashcroft DM, O\u2019Neill TW (2021) Incidence of paget\u2019s disease of bone in the UK: evidence of a continuing decline. Rheumatology (Oxford). https:\/\/doi.org\/10.1093\/rheumatology\/keab232","journal-title":"Rheumatology (Oxford)"},{"key":"1279_CR2","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1007\/s00223-014-9904-1","volume":"95","author":"A Tan","year":"2014","unstructured":"Tan A, Ralston SH (2014) Clinical presentation of paget\u2019s disease: evaluation of a contemporary cohort and systematic review. Calcif Tissue Int 95:385\u2013392. https:\/\/doi.org\/10.1007\/s00223-014-9904-1","journal-title":"Calcif Tissue Int"},{"key":"1279_CR3","doi-asserted-by":"publisher","first-page":"634","DOI":"10.1007\/s00223-020-00800-5","volume":"108","author":"JA Walker","year":"2021","unstructured":"Walker JA, Tuck SP (2021) Paget\u2019s disease of the bone: patterns of referral to secondary care following diagnosis on X-rays. Calcif Tissue Int 108:634\u2013639. https:\/\/doi.org\/10.1007\/s00223-020-00800-5","journal-title":"Calcif Tissue Int"},{"key":"1279_CR4","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1359\/jbmr.090709","volume":"25","author":"AL Langston","year":"2010","unstructured":"Langston AL, Campbell MK, Fraser WD, MacLennan GS, Selby PL, Ralston SH (2010) Randomised trial of intensive bisphosphonate treatment versus symptomatic management in paget\u2019s disease of bone. J. Bone Miner. Res 25:20\u201331. https:\/\/doi.org\/10.1359\/jbmr.090709","journal-title":"J. Bone Miner. Res"},{"key":"1279_CR5","doi-asserted-by":"publisher","first-page":"1165","DOI":"10.1002\/jbmr.3066","volume":"32","author":"A Tan","year":"2017","unstructured":"Tan A, Goodman K, Walker A, Hudson J, MacLennan GS, Selby PL, Fraser WD, Ralston SH, Group P-ET (2017) Long-term randomized trial of intensive versus symptomatic management in paget\u2019s disease of bone: the PRISM-EZ Study. J Bone Miner Res 32:1165\u20131173. https:\/\/doi.org\/10.1002\/jbmr.3066","journal-title":"J Bone Miner Res"},{"key":"1279_CR6","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1016\/s8756-3282(02)00817-7","volume":"31","author":"PL Selby","year":"2002","unstructured":"Selby PL, Davie MW, Ralston SH, Stone MD, Bone, Tooth Society of Great B, National Association for the Relief of Paget\u2019s D (2002) Guidelines on the management of Paget\u2019s disease of bone. Bone 31:366\u2013373. https:\/\/doi.org\/10.1016\/s8756-3282(02)00817-7","journal-title":"Bone"},{"key":"1279_CR7","doi-asserted-by":"publisher","first-page":"903","DOI":"10.1016\/s0895-4356(98)00081-x","volume":"51","author":"JE Ware Jr","year":"1998","unstructured":"Ware JE Jr, Gandek B (1998) Overview of the SF-36 health survey and the international quality of life assessment (IQOLA) project. J Clin. Epidemiol 51:903\u2013912. https:\/\/doi.org\/10.1016\/s0895-4356(98)00081-x","journal-title":"J Clin. Epidemiol"},{"key":"1279_CR8","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/S0304-3959(00)00482-6","volume":"92","author":"M Bennett","year":"2001","unstructured":"Bennett M (2001) The LANSS pain scale: the leeds assessment of neuropathic symptoms and signs. Pain 92:147\u2013157","journal-title":"Pain"},{"key":"1279_CR9","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1172\/JCI115584","volume":"89","author":"GD Roodman","year":"1992","unstructured":"Roodman GD, Kurihara N, Ohsaki Y, Kukita A, Hosking D, Demulder A, Smith JF, Singer FR (1992) Interleukin 6. a potential autocrine\/paracrine factor in Paget\u2019s disease of bone. J Clin Invest 89:46\u201352. https:\/\/doi.org\/10.1172\/JCI115584","journal-title":"J Clin Invest"},{"key":"1279_CR10","doi-asserted-by":"publisher","first-page":"1664","DOI":"10.1097\/j.pain.0000000000001260","volume":"159","author":"D Rendina","year":"2018","unstructured":"Rendina D, De Filippo G, Postiglione L, Covelli B, Ricciardone M, Guillaume S, Di Spigna G, Selleri C, Merlotti D, Bianciardi S, Materozzi M, Muscariello R, De Pascale F, D\u2019Elia L, Nuti R, Strazzullo P, Gennari L (2018) Interleukin-6 trans-signaling and pathological low back pain in patients with paget disease of bone. Pain 159:1664\u20131673. https:\/\/doi.org\/10.1097\/j.pain.0000000000001260","journal-title":"Pain"},{"key":"1279_CR11","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1016\/S8756-3282(00)00453-1","volume":"28","author":"Y Fujikawa","year":"2001","unstructured":"Fujikawa Y, Sabokbar A, Neale SD, Itonaga I, Torisu T, Athanasou NA (2001) The effect of macrophage-colony stimulating factor and other humoral factors (interleukin\u22121, \u22123, \u22126, and \u221211, tumor necrosis factor-alpha, and granulocyte macrophage-colony stimulating factor) on human osteoclast formation from circulating cells. Bone 28:261\u2013267","journal-title":"Bone"},{"key":"1279_CR12","doi-asserted-by":"publisher","first-page":"1121","DOI":"10.1002\/art.1780231008","volume":"23","author":"RD Altman","year":"1980","unstructured":"Altman RD (1980) Musculoskeletal manifestations of paget\u2019s disease of bone. Arthr Rheum 23:1121\u20131127","journal-title":"Arthr Rheum"},{"key":"1279_CR13","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1359\/jbmr.2002.17.3.465","volume":"17","author":"TP van Staa","year":"2002","unstructured":"van Staa TP, Selby P, Leufkens HG, Lyles K, Sprafka JM, Cooper C (2002) Incidence and natural history of paget\u2019s disease of bone in England and Wales. J. Bone Miner. Res 17:465\u2013471. https:\/\/doi.org\/10.1359\/jbmr.2002.17.3.465","journal-title":"J. Bone Miner. Res"},{"key":"1279_CR14","doi-asserted-by":"publisher","first-page":"1061","DOI":"10.1093\/rheumatology\/34.11.1061","volume":"34","author":"PS Helliwell","year":"1995","unstructured":"Helliwell PS (1995) Osteoarthritis and paget\u2019s disease. Br J Rheumatol 34:1061\u20131063. https:\/\/doi.org\/10.1093\/rheumatology\/34.11.1061","journal-title":"Br J Rheumatol"},{"key":"1279_CR15","doi-asserted-by":"publisher","first-page":"e010364","DOI":"10.1136\/bmjopen-2015-010364","volume":"6","author":"A Fayaz","year":"2016","unstructured":"Fayaz A, Croft P, Langford RM, Donaldson LJ, Jones GT (2016) Prevalence of chronic pain in the UK: a systematic review and meta-analysis of population studies. BMJ Open 6:e010364. https:\/\/doi.org\/10.1136\/bmjopen-2015-010364","journal-title":"BMJ Open"},{"key":"1279_CR16","doi-asserted-by":"publisher","first-page":"2327","DOI":"10.1002\/jbmr.3873","volume":"34","author":"SH Ralston","year":"2019","unstructured":"Ralston SH, Corral-Gudino L, Cooper C, Francis RM, Fraser WD, Gennari L, Guanabens N, Javaid MK, Layfield R, O\u2019Neill TW, Russell RGG, Stone MD, Simpson K, Wilkinson D, Wills R, Zillikens MC, Tuck SP (2019) Clinical guidelines on paget\u2019s disease of bone. J Bone Miner Res 34:2327\u20132329. https:\/\/doi.org\/10.1002\/jbmr.3873","journal-title":"J Bone Miner Res"},{"key":"1279_CR17","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1056\/NEJMoa044241","volume":"353","author":"IR Reid","year":"2005","unstructured":"Reid IR, Miller P, Lyles K, Fraser W, Brown JP, Saidi Y, Mesenbrink P, Su G, Pak J, Zelenakas K, Luchi M, Richardson P, Hosking D (2005) Comparison of a single infusion of zoledronic acid with risedronate for Paget\u2019s disease. N Engl J Med 353:898\u2013908. https:\/\/doi.org\/10.1056\/NEJMoa044241","journal-title":"N Engl J Med"},{"key":"1279_CR18","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1093\/qjmed\/95.4.233","volume":"95","author":"SD Neale","year":"2002","unstructured":"Neale SD, Schulze E, Smith R, Athanasou NA (2002) The influence of serum cytokines and growth factors on osteoclast formation in paget\u2019s disease. QJM 95:233\u2013240","journal-title":"QJM"},{"key":"1279_CR19","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1007\/s002239900254","volume":"60","author":"VM Natale","year":"1997","unstructured":"Natale VM, Filho WJ, Duarte AJ (1997) Cellular immunity aspects in elderly subjects with Paget\u2019s disease of bone. Calcif. Tissue Int 60:410\u2013414","journal-title":"Calcif. Tissue Int"},{"key":"1279_CR20","doi-asserted-by":"publisher","first-page":"824","DOI":"10.1002\/art.10834","volume":"48","author":"L Alvarez","year":"2003","unstructured":"Alvarez L, Peris P, Guanabens N, Vidal S, Ros I, Pons F, Filella X, Monegal A, Munoz-Gomez J, Ballesta AM (2003) Serum osteoprotegerin and its ligand in paget\u2019s disease of bone: relationship to disease activity and effect of treatment with bisphosphonates. Arthritis Rheum 48:824\u2013828","journal-title":"Arthritis Rheum"},{"key":"1279_CR21","doi-asserted-by":"publisher","first-page":"6762","DOI":"10.1074\/jbc.RA117.001163","volume":"293","author":"P Baran","year":"2018","unstructured":"Baran P, Hansen S, Waetzig GH, Akbarzadeh M, Lamertz L, Huber HJ, Ahmadian MR, Moll JM, Scheller J (2018) The balance of interleukin (IL)-6, IL-6.soluble IL-6 receptor (sIL-6R), and IL-6.sIL-6R.sgp130 complexes allows simultaneous classic and trans-signaling. J Biol Chem 293:6762\u20136775. https:\/\/doi.org\/10.1074\/jbc.RA117.001163","journal-title":"J Biol Chem"},{"key":"1279_CR22","doi-asserted-by":"publisher","first-page":"520","DOI":"10.1038\/ng.562","volume":"42","author":"OM Albagha","year":"2010","unstructured":"Albagha OM, Visconti MR, Alonso N, Langston AL, Cundy T, Dargie R, Dunlop MG, Fraser WD, Hooper MJ, Isaia G, Nicholson GC, Del Pino MJ, Gonzalez-Sarmiento R, Di SM, Tenesa A, Walsh JP, Ralston SH (2010) Genome-wide association study identifies variants at CSF1, OPTN and TNFRSF11A as genetic risk factors for paget\u2019s disease of bone. Nat. Genet 42:520\u2013524","journal-title":"Nat. Genet"},{"key":"1279_CR23","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1038\/ng.845","volume":"43","author":"OM Albagha","year":"2011","unstructured":"Albagha OM, Wani SE, Visconti MR, Alonso N, Goodman K, Brandi ML, Cundy T, Chung PY, Dargie R, Devogelaer JP, Falchetti A, Fraser WD, Gennari L, Gianfrancesco F, Hooper MJ, Van Hul W, Isaia G, Nicholson GC, Nuti R, Papapoulos S, Montes Jdel P, Ratajczak T, Rea SL, Rendina D, Gonzalez-Sarmiento R, Di Stefano M, Ward LC, Walsh JP, Ralston SH, Genetic Determinants of Paget\u2019s Disease C (2011) Genome-wide association identifies three new susceptibility loci for Paget\u2019s disease of bone. Nat Genet 43:685\u2013689. https:\/\/doi.org\/10.1038\/ng.845","journal-title":"Nat Genet"},{"key":"1279_CR24","first-page":"CD004956","volume":"12","author":"L Corral-Gudino","year":"2017","unstructured":"Corral-Gudino L, Tan AJ, Del Pino-Montes J, Ralston SH (2017) Bisphosphonates for Paget\u2019s disease of bone in adults. Cochrane Database Syst Rev 12:CD004956","journal-title":"Cochrane Database Syst Rev"}],"container-title":["Calcified Tissue International"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00223-024-01279-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00223-024-01279-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00223-024-01279-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,2]],"date-time":"2024-11-02T22:04:52Z","timestamp":1730585092000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00223-024-01279-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,30]]},"references-count":24,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["1279"],"URL":"https:\/\/doi.org\/10.1007\/s00223-024-01279-0","relation":{},"ISSN":["1432-0827"],"issn-type":[{"value":"1432-0827","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,30]]},"assertion":[{"value":"5 June 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 August 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 September 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"William D Fraser reports funding to his institution from Novartis, Takeda, NPS Pharma, Sanofi, Amolyt and Entera-Bio Pharma outside the submitted work and donation of assay materials and evaluation kits from Abbot Diagnostics outside the submitted work; Jonathan C Y Tang reports participating in advisory boards for NPS Pharma, Amolyt and Entera-Biopharma; having received assay materials from Abbott Diagnostics; having received funding to his institution from Novartis, Takeda, NPS Pharma and Sanofi; and honoraria from Novartis, Sanofi and Ascendis outside the submitted work. Eugene McCloskey reports receiving honoraria from Amgen, Thornton & Ross and Flynn Pharma outside the submitted work. Stuart H Ralston reports funding to his institution from Kyowa Kirin, UCB, and the Royal Osteoporosis Society outside the submitted work. The remaining authors have no conflicts of interest to report.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"This research was conducted with the approval of the West of Scotland Research Ethics Committee 3 (18\/WS\/0236) and all participants gave written informed consent prior to taking part.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed Consent"}},{"value":"The study did not involve experimental animals.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Human and Animal Rights"}}]}}