Randomised trial of genetic testing and targeted intervention to prevent the development and progression of Paget’s disease of bone

• Published in: Annals of the rheumatic diseases Vol. 83; no. 4; pp. 529 - 536
• Main Authors: Phillips, Jonathan, Subedi, Deepak, Lewis, Steff C, Keerie, Catriona, Cronin, Owen, Porteous, Mary, Moore, David, Cetnarskyj, Roseanne, Ranganath, Lakshminarayan, Selby, Peter L, Turgut, Tolga, Hampson, Geeta, Chandra, Rama, Ho, Shu, Tobias, Jon, Young-Min, Steven, McKenna, Malachi J, Crowley, Rachel K, Fraser, William D, Tang, Jonathan C Y, Gennari, Luigi, Nuti, Rannuccio, Brandi, Maria Luisa, Del Pino-Montes, Javier, Devogelaer, Jean-Pierre, Durnez, Anne, Isaia, Giovanni Carlo, Di Stefano, Marco, Guanabens, Nuria, Blanch Rubio, Josep, Seibel, Markus J, Walsh, John P, Rea, Sarah L, Kotowicz, Mark A, Nicholson, Geoffrey C, Duncan, Emma L, Major, Gabor, Horne, Anne, Gilchrist, Nigel, Ralston, Stuart H
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd and European League Against Rheumatism 01.04.2024; BMJ Publishing Group LTD
• Subjects: Biochemical markers; Biomarkers; Bisphosphonates; Bone lesions; Bone turnover; Cross-sectional studies; Diphosphonates - adverse effects; Disease prevention; Family medical history; Genetic screening; Genetic Testing; Humans; Intervention; Miscellaneous; Osteitis Deformans - complications; Osteitis Deformans - drug therapy; Osteitis Deformans - genetics; Patient Reported Outcome Measures; Pharmacogenetics; Phosphatase; Placebos; Scintigraphy; Sequestosome-1 Protein - genetics; Therapeutics; Zoledronic acid; Zoledronic Acid - therapeutic use; Pharmacogenetics; Therapeutics; Patient Reported Outcome Measures
• ISSN: 0003-4967; 1468-2060
• DOI: 10.1136/ard-2023-224990

IntroductionPaget’s disease of bone (PDB) frequently presents at an advanced stage with irreversible skeletal damage. Clinical outcomes might be improved by earlier diagnosis and prophylactic treatment.MethodsWe randomised 222 individuals at increased risk of PDB because of pathogenic SQSTM1 variants to receive 5 mg zoledronic acid (ZA) or placebo. The primary outcome was new bone lesions assessed by radionuclide bone scan. Secondary outcomes included change in existing lesions, biochemical markers of bone turnover and skeletal events related to PDB.ResultsThe median duration of follow-up was 84 months (range 0–127) and 180 participants (81%) completed the study. At baseline, 9 (8.1%) of the ZA group had PDB lesions vs 12 (10.8%) of the placebo group. Two of the placebo group developed new lesions versus none in the ZA group (OR 0.41, 95% CI 0.00 to 3.43, p=0.25). Eight of the placebo group had a poor outcome (lesions which were new, unchanged or progressing) compared with none of the ZA group (OR 0.08, 95% CI 0.00 to 0.42, p=0.003). At the study end, 1 participant in the ZA group had lesions compared with 11 in the placebo group. Biochemical markers of bone turnover were significantly reduced in the ZA group. One participant allocated to placebo required rescue therapy with ZA because of symptomatic disease. The number and severity of adverse events did not differ between groups.ConclusionsGenetic testing for pathogenic SQSTM1 variants coupled with intervention with ZA is well tolerated and has favourable effects on the progression of early PDB.Trial registration number ISRCTN11616770.