Randomized Controlled Trial

. 2024 Mar 12;83(4):529-536.

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 Phillips¹, Deepak Subedi², Steff C Lewis³, Catriona Keerie³, Owen Cronin^{4

5}, Mary Porteous¹, David Moore⁶, Roseanne Cetnarskyj⁷, Lakshminarayan Ranganath⁸, Peter L Selby⁹, Tolga Turgut¹⁰, Geeta Hampson¹¹, Rama Chandra¹², Shu Ho^{13

14}, Jon Tobias¹⁵, Steven Young-Min¹⁶, Malachi J McKenna¹⁷, Rachel K Crowley^{17

18}, William D Fraser¹⁹, Jonathan C Y Tang²⁰, Luigi Gennari²¹, Rannuccio Nuti²¹, Maria Luisa Brandi^{22

23}, Javier Del Pino-Montes²⁴, Jean-Pierre Devogelaer²⁵, Anne Durnez^{25

26}, Giovanni Carlo Isaia²⁷, Marco Di Stefano²⁷, Nuria Guanabens²⁸, Josep Blanch Rubio²⁹, Markus J Seibel³⁰, John P Walsh³¹, Sarah L Rea^{31

32

33}, Mark A Kotowicz^{34

35

36}, Geoffrey C Nicholson³⁷, Emma L Duncan^{38

39

40}, Gabor Major^{41

42}, Anne Horne⁴³, Nigel Gilchrist⁴⁴, Stuart H Ralston⁴⁵

Affiliations

¹ Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, Western General Hospital, University of Edinburgh, Edinburgh, UK.
² Department of Radiology and Nuclear Medicine, Western General Hospital, Edinburgh, UK.
³ Edinburgh Clinical Trials Unit, The Usher Institute, The University of Edinburgh, Edinburgh, UK.
⁴ Rheumatic Diseases Unit, Western General Hospital, Edinburgh, UK.
⁵ School of Medicine, University College Cork, University College Cork, National University of Ireland, Cork, Ireland.
⁶ South East Scotland Molecular Genetics Service, NHS Lothian, Edinburgh, UK.
⁷ School of Health Sciences, University of Dundee, Dundee, UK.
⁸ Clinical Biochemistry and Metabolic Medicine, University of Liverpool, Liverpool, UK.
⁹ Department of Diabetes, Endocrinology and Metabolism, Manchester Royal Infirmary, Manchester, UK.
¹⁰ Clinical Genetics, Manchester Centre for Genomic Medicine, Manchester University Hospitals Foundation NHS Trust, Manchester, UK.
¹¹ Department of Chemical Pathology, St Thomas' Hospital, London, UK.
¹² King's College Hospital, London, UK.
¹³ Rheumatology, Robert Jones and Agnes Hunt Orthopaedic and District Hospital NHS Trust, Oswestry, UK.
¹⁴ Shrewsbury and Telford Hospital NHS Trust, Shrewsbury, UK.
¹⁵ Musculoskeletal Research Unit, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
¹⁶ Queen Alexandra Hospital, Portsmouth, UK.
¹⁷ Department of Endocrinology and Diabetes Mellitus, St Vincent's University Hospital, Dublin, Ireland.
¹⁸ Rare Disease Clinical Trial Network, University College Dublin, Dublin, Ireland.
¹⁹ Norwich Medical School, University of East Anglia, Norwich, UK.
²⁰ Departments of Endocrinology and Clinical Biochemistry, University of East Anglia, Norwich, UK.
²¹ Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.
²² FIRMO Foundation, Florence, Italy.
²³ Bone Centre, Università Vita-Salute San Raffaele, Milan, Italy.
²⁴ Rheumatology, University of Salamanca, Salamanca, Spain.
²⁵ Department of Rheumatology, Saint-Luc University Hospital, Université catholique de Louvain, Brussels, Belgium.
²⁶ Department of Rheumatology, AZ Jan Portaels Hospital, Vilvoorde, Belgium.
²⁷ University of Turin, Turin, Italy.
²⁸ Department of Rheumatology, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain.
²⁹ Rheumatology Department, Hospital del Mar, Barcelona, Spain.
³⁰ Concord Repatriation General Hospital, Concord, New South Wales, Australia.
³¹ Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
³² Centre for Molecular Medicine and Innovative Therapeutics, Health Futures Institute, Murdoch University, Perth, Western Australia, Australia.
³³ Perron Institute for Neurological and Translational Science, Perth, Western Australia, Australia.
³⁴ Institute for Mental and Physical Health and Clinical Translation, Deakin University, Geelong, Victoria, Australia.
³⁵ Department of Medicine at Western Health, The University of Melbourne, St Albans, Victoria, Australia.
³⁶ University Hospital Geelong, Barwon Health, Geelong, Victoria, Australia.
³⁷ Rural Clinical School, The University of Queensland, Toowoomba, Queensland, Australia.
³⁸ Endocrinology Department, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia.
³⁹ School of Life Course & Population Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK.
⁴⁰ Department of Endocrinology, Guy's and St Thomas' NHS Foundation Trust, London, UK.
⁴¹ Rheumatology, John Hunter Hospital, New Lambton Heights, New South Wales, Australia.
⁴² Faculty of Medicine, The University of Newcastle, Callaghan, New South Wales, Australia.
⁴³ Department of Medicine, The University of Auckland, Auckland, New Zealand.
⁴⁴ Princess Margaret Hospital, Christchurch, New Zealand.
⁴⁵ Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, Western General Hospital, University of Edinburgh, Edinburgh, UK stuart.ralston@ed.ac.uk.

PMID: 38123339
PMCID: PMC10958267
DOI: 10.1136/ard-2023-224990

Randomized Controlled Trial

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

Jonathan Phillips et al. Ann Rheum Dis. 2024.

. 2024 Mar 12;83(4):529-536.

doi: 10.1136/ard-2023-224990.

Authors

Affiliations

¹ Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, Western General Hospital, University of Edinburgh, Edinburgh, UK.
² Department of Radiology and Nuclear Medicine, Western General Hospital, Edinburgh, UK.
³ Edinburgh Clinical Trials Unit, The Usher Institute, The University of Edinburgh, Edinburgh, UK.
⁴ Rheumatic Diseases Unit, Western General Hospital, Edinburgh, UK.
⁵ School of Medicine, University College Cork, University College Cork, National University of Ireland, Cork, Ireland.
⁶ South East Scotland Molecular Genetics Service, NHS Lothian, Edinburgh, UK.
⁷ School of Health Sciences, University of Dundee, Dundee, UK.
⁸ Clinical Biochemistry and Metabolic Medicine, University of Liverpool, Liverpool, UK.
⁹ Department of Diabetes, Endocrinology and Metabolism, Manchester Royal Infirmary, Manchester, UK.
¹⁰ Clinical Genetics, Manchester Centre for Genomic Medicine, Manchester University Hospitals Foundation NHS Trust, Manchester, UK.
¹¹ Department of Chemical Pathology, St Thomas' Hospital, London, UK.
¹² King's College Hospital, London, UK.
¹³ Rheumatology, Robert Jones and Agnes Hunt Orthopaedic and District Hospital NHS Trust, Oswestry, UK.
¹⁴ Shrewsbury and Telford Hospital NHS Trust, Shrewsbury, UK.
¹⁵ Musculoskeletal Research Unit, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
¹⁶ Queen Alexandra Hospital, Portsmouth, UK.
¹⁷ Department of Endocrinology and Diabetes Mellitus, St Vincent's University Hospital, Dublin, Ireland.
¹⁸ Rare Disease Clinical Trial Network, University College Dublin, Dublin, Ireland.
¹⁹ Norwich Medical School, University of East Anglia, Norwich, UK.
²⁰ Departments of Endocrinology and Clinical Biochemistry, University of East Anglia, Norwich, UK.
²¹ Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.
²² FIRMO Foundation, Florence, Italy.
²³ Bone Centre, Università Vita-Salute San Raffaele, Milan, Italy.
²⁴ Rheumatology, University of Salamanca, Salamanca, Spain.
²⁵ Department of Rheumatology, Saint-Luc University Hospital, Université catholique de Louvain, Brussels, Belgium.
²⁶ Department of Rheumatology, AZ Jan Portaels Hospital, Vilvoorde, Belgium.
²⁷ University of Turin, Turin, Italy.
²⁸ Department of Rheumatology, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain.
²⁹ Rheumatology Department, Hospital del Mar, Barcelona, Spain.
³⁰ Concord Repatriation General Hospital, Concord, New South Wales, Australia.
³¹ Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
³² Centre for Molecular Medicine and Innovative Therapeutics, Health Futures Institute, Murdoch University, Perth, Western Australia, Australia.
³³ Perron Institute for Neurological and Translational Science, Perth, Western Australia, Australia.
³⁴ Institute for Mental and Physical Health and Clinical Translation, Deakin University, Geelong, Victoria, Australia.
³⁵ Department of Medicine at Western Health, The University of Melbourne, St Albans, Victoria, Australia.
³⁶ University Hospital Geelong, Barwon Health, Geelong, Victoria, Australia.
³⁷ Rural Clinical School, The University of Queensland, Toowoomba, Queensland, Australia.
³⁸ Endocrinology Department, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia.
³⁹ School of Life Course & Population Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK.
⁴⁰ Department of Endocrinology, Guy's and St Thomas' NHS Foundation Trust, London, UK.
⁴¹ Rheumatology, John Hunter Hospital, New Lambton Heights, New South Wales, Australia.
⁴² Faculty of Medicine, The University of Newcastle, Callaghan, New South Wales, Australia.
⁴³ Department of Medicine, The University of Auckland, Auckland, New Zealand.
⁴⁴ Princess Margaret Hospital, Christchurch, New Zealand.
⁴⁵ Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, Western General Hospital, University of Edinburgh, Edinburgh, UK stuart.ralston@ed.ac.uk.

PMID: 38123339
PMCID: PMC10958267
DOI: 10.1136/ard-2023-224990

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.

Keywords: Patient Reported Outcome Measures; Pharmacogenetics; Therapeutics.

PubMed Disclaimer

Conflict of interest statement

Competing interests: DS reports receiving honoraria from GE Healthcare outside the submitted work; OC reports receiving lecture fees from Nordic Pharma and financial support for attending conferences from Abbvie, outside the submitted work; GH reports funding from the Royal Osteoporosis Society to her institution and honoraria from Amgen and UCB outside the submitted work; JT reports funding to his institution from the Wellcome trust and Medical Research Council, outside the submitted work and that he is chair of the Royal Osteoporosis Society Research and Innovation grant assessment panel; SYM report receiving lecture fees from Janssen Pharmaceuticals outside the submitted work; RC reports funding to her institution from Kyowa Kirin and Amgen outside the submitted work; WDF 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; NG reports receiving honoraria from Amgen, UCB, Lilly and Gedeon Richter and support from UCB for attending conferences outside the submitted work; MJS reports funding to his institution from Amgen and Allergen outside the submitted work and funding from the National Health and Medical Research Council of Australia to his institution outside the submitted work; MKK reports funding to his institution from the Medical Research Futures Fund; GM is a member of the Scientific Advisory Board of Osteoporosis Australia; SHR reports funding to his institution from Kyowa Kirin, UCB, the Paget’s Association and the Royal Osteoporosis Society outside the submitted work. The other authors have no interests to declare.

Figures

**Figure 1**
Disposition of study population.

**Figure 2**
Changes in biochemical markers of bone turnover. The baseline values at month 0 are the means. Subsequent values are adjusted least squares means and 95% CIs. The p values refer to differences between the groups assessed by repeated measures ANOVA over the whole duration of the study. Unified reference ranges for men and women of all ages are indicated by the interrupted horizontal lines. Measurements of CTX were available in 103 of the ZA group at baseline, 100 at 12 months, 97 at 24 months, 96 at 36 months, 75 at 48 months, 62 at 60 months and 89 at the end of study. Corresponding values for the placebo group were 101, 97, 91, 93, 74, 50 and 89. For PINP, numbers in the ZA group were 103, 100, 97, 96, 75, 62 and 89; and in the placebo group, 101, 97, 91, 96, 74, 50 and 89. ANOVA, analysis of variance; CTX, type I collagen C-telopeptides; PINP, procollagen type I amino-terminal propeptides.

See this image and copyright information in PMC

References

1. van Staa TP, Selby P, Leufkens HGM, et al. . Incidence and natural history of Paget's disease of bone in England and Wales. J Bone Miner Res 2002;17:465–71. 10.1359/jbmr.2002.17.3.465 - DOI - PubMed
1. Ralston SH. Clinical practice. Paget's disease of bone. N Engl J Med 2013;368:644–50. 10.1056/NEJMcp1204713 - DOI - PubMed
1. Ralston SH. Bisphosphonates in the management of Paget's disease. Bone 2020;138. 10.1016/j.bone.2020.115465 - DOI - PubMed
1. Tan A, Goodman K, Walker A, et al. . Long-term randomized trial of intensive versus symptomatic management in Paget's disease of bone: the PRISM-EZ study. J Bone Miner Res 2017;32:1165–73. 10.1002/jbmr.3066 - DOI - PubMed
1. Langston AL, Campbell MK, Fraser WD, et al. . Randomized trial of intensive bisphosphonate treatment versus symptomatic management in Paget's disease of bone. J Bone Miner Res 2010;25:20–31. 10.1359/jbmr.090709 - DOI - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources