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

Jonathan Phillips, Deepak Subedi, Steff C Lewis, Catriona Keerie, Owen Cronin, Mary Porteous, David Moore, Roseanne Cetnarskyj, Lakshminarayan Ranganath, Peter L. Selby, Tolga Turgut, Geeta Hampson, Rama Chandra, Shu Ho, Jon Tobias, Steven Young-Min, Malachi J McKenna, Rachel K Crowley, William D Fraser, Jonathan C Y TangLuigi Gennari, Rannuccio Nuti, Maria Luisa Brandi, Javier Del Pino-Montes, Jean-Pierre Devogelaer, Anne Durnez, Giovanni Carlo Isaia, Marco Di Stefano, Nuria Guanabens, Josep Blanch Rubio, Markus J Seibel, John P Walsh, Sarah L Rea, Mark A Kotowicz, Geoffrey C Nicholson, Emma L Duncan, Gabor Major, Anne Horne, Nigel Gilchrist, Stuart H Ralston

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INTRODUCTION: Paget'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.

METHODS: We 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.

RESULTS: The 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.

CONCLUSIONS: Genetic testing for pathogenic SQSTM1 variants coupled with intervention with ZA is well tolerated and has favourable effects on the progression of early PDB.


Original languageEnglish
Article number224990
Pages (from-to)1-8
Number of pages8
JournalAnnals of the Rheumatic Diseases
Early online date20 Dec 2023
Publication statusE-pub ahead of print - 20 Dec 2023


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