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 Tang; Luigi 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

doi:10.1136/ard-2023-224990

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

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

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.

TRIAL REGISTRATION NUMBER: ISRCTN11616770.

Original language	English
Journal	Annals of the Rheumatic Diseases
Early online date	20 Dec 2023
DOIs	https://doi.org/10.1136/ard-2023-224990
Publication status	E-pub ahead of print - 20 Dec 2023

Access to Document

10.1136/ard-2023-224990Licence: Creative Commons: Attribution (CC-BY)

OA_ard-2023-224990.full
Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.
Final published version, 1.45 MBLicence: Creative Commons: Attribution (CC-BY)

Cite this

Phillips, J., Subedi, D., Lewis, S. C., Keerie, C., Cronin, O., Porteous, M., Moore, D., Cetnarskyj, R., Ranganath, L., Selby, P. L., Turgut, T., Hampson, G., Chandra, R., Ho, S., Tobias, J., Young-Min, S., McKenna, M. J., Crowley, R. K., Fraser, W. D., ... Ralston, S. H. (2023). Randomised trial of genetic testing and targeted intervention to prevent the development and progression of Paget's disease of bone. Annals of the Rheumatic Diseases. Advance online publication. https://doi.org/10.1136/ard-2023-224990

@article{a00841bac7084aa8bfce61bf92d6159f,

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

abstract = "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.TRIAL REGISTRATION NUMBER: ISRCTN11616770.",

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

note = "{\textcopyright} Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.",

year = "2023",

month = dec,

day = "20",

doi = "10.1136/ard-2023-224990",

language = "English",

journal = "Annals of the Rheumatic Diseases",

issn = "0003-4967",

publisher = "BMJ Publishing Group",

}

Phillips, J, Subedi, D, Lewis, SC , Keerie, C, Cronin, O, Porteous, M, Moore, D, Cetnarskyj, R, Ranganath, L, Selby, PL, Turgut, T, Hampson, G, Chandra, R, Ho, S, Tobias, J, Young-Min, S, McKenna, MJ, Crowley, RK, Fraser, WD, Tang, JCY, Gennari, L, Nuti, R, Brandi, ML, Del Pino-Montes, J, Devogelaer, J-P, Durnez, A, Isaia, GC, Di Stefano, M, Guanabens, N, Blanch Rubio, J, Seibel, MJ, Walsh, JP, Rea, SL, Kotowicz, MA, Nicholson, GC, Duncan, EL, Major, G, Horne, A, Gilchrist, N & Ralston, SH 2023, 'Randomised trial of genetic testing and targeted intervention to prevent the development and progression of Paget's disease of bone', Annals of the Rheumatic Diseases. https://doi.org/10.1136/ard-2023-224990

TY - JOUR

T1 - Randomised trial of genetic testing and targeted intervention to prevent the development and progression of Paget's disease of bone

AU - Phillips, Jonathan

AU - Subedi, Deepak

AU - Lewis, Steff C

AU - Keerie, Catriona

AU - Cronin, Owen

AU - Porteous, Mary

AU - Moore, David

AU - Cetnarskyj, Roseanne

AU - Ranganath, Lakshminarayan

AU - Selby, Peter L

AU - Turgut, Tolga

AU - Hampson, Geeta

AU - Chandra, Rama

AU - Ho, Shu

AU - Tobias, Jon

AU - Young-Min, Steven

AU - McKenna, Malachi J

AU - Crowley, Rachel K

AU - Fraser, William D

AU - Tang, Jonathan C Y

AU - Gennari, Luigi

AU - Nuti, Rannuccio

AU - Brandi, Maria Luisa

AU - Del Pino-Montes, Javier

AU - Devogelaer, Jean-Pierre

AU - Durnez, Anne

AU - Isaia, Giovanni Carlo

AU - Di Stefano, Marco

AU - Guanabens, Nuria

AU - Blanch Rubio, Josep

AU - Seibel, Markus J

AU - Walsh, John P

AU - Rea, Sarah L

AU - Kotowicz, Mark A

AU - Nicholson, Geoffrey C

AU - Duncan, Emma L

AU - Major, Gabor

AU - Horne, Anne

AU - Gilchrist, Nigel

AU - Ralston, Stuart H

PY - 2023/12/20

Y1 - 2023/12/20

N2 - 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.TRIAL REGISTRATION NUMBER: ISRCTN11616770.

AB - 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.TRIAL REGISTRATION NUMBER: ISRCTN11616770.

U2 - 10.1136/ard-2023-224990

DO - 10.1136/ard-2023-224990

M3 - Article

C2 - 38123339

SN - 0003-4967

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

ER -

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

Abstract / Description of output

Access to Document

Fingerprint

Cite this