Characteristics of early Paget's disease in SQSTM1 mutation carriers: Baseline analysis of the ZiPP study cohort

Owen Cronin; Deepak Subedi; Laura Forsyth; Kirsteen Goodman; Steff C Lewis; Catriona Keerie; Allan Walker; Mary Porteous; Roseanne Cetnarskyj; Ranganath Lakshminarayan; Peter Selby; Geeta Hampson; Rama Chandra; Shu Ho; Jon Tobias; Steven Young Min; Malachi McKenna; Rachel Crowley; William D Fraser; Jonathan Tang; Luigi Gennari; Rannuccio Nuti; Maria-Luisa Brandi; Javier Del Pino-Montes; Jean-Pierre Devogelaer; Anne Durnez; Giovanni Carlo Isaia; Marco Di Stefano; Josep Blanch Rubio; Nuria Guanabens; Markus Seibel; John P Walsh; Mark A Kotowicz; Geoffrey C Nicholson; Emma L Duncan; Gabor Major; Ann Horne; Nigel Gilchrist; Stuart H Ralston

doi:10.1002/jbmr.4007

Characteristics of early Paget's disease in SQSTM1 mutation carriers: Baseline analysis of the ZiPP study cohort

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

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Abstract / Description of output

OBJECTIVES: Mutations in SQSTM1 are strongly associated with Paget's disease of bone (PDB) but little is known about the clinical characteristics of those with early disease.

METHODS: Radionuclide bone scans, biochemical markers of bone turnover and clinical characteristics were analysed in SQSTM1 mutation carriers who took part in the Zoledronic acid in the Prevention of Paget's disease (ZiPP) study.

RESULTS: We studied 222 individuals of whom 54.9% were female with average (± sem) age of 50.1± 0.6 years. Twelve SQSTM1 mutations were observed, including p.Pro392Leu which was present in 141/222 (63.5%) subjects. Bone scan examination revealed evidence of PDB in 20 subjects (9.0%) of which 9 (50%) had a single affected site. Participants with lesions were older than those without lesions but the difference was not significant (53.6 ± 9.1 vs. 49.8 ± 8.9, p=0.07). The mean age of participants with lesions was not significantly different from the age at which their parents were diagnosed with PDB (55 years vs. 59 years, p=0.25). All individuals with lesions were asymptomatic. Serum concentrations of total alkaline phosphatase (ALP) normalised to the upper limit of normal in each centre were higher in those with lesions (0.75 ± 0.69 vs 0.42 ± 0.29; p<0.0001). Similar findings were observed for other biochemical markers of bone turnover but the sensitivity of ALP and other markers in detecting lesions was poor.

CONCLUSIONS: Asymptomatic PDB is present in about 9% of SQSTM1 mutation carriers by the fifth decade. Further follow up of this cohort will provide important information on the natural history of early PDB and its response to treatment. This article is protected by copyright. All rights reserved.

Original language	English
Journal	Journal of Bone and Mineral Research
Early online date	16 Mar 2020
DOIs	https://doi.org/10.1002/jbmr.4007
Publication status	E-pub ahead of print - 16 Mar 2020

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AAM_Cronin ZIPP Baseline study Rev1 170220 cleanAccepted author manuscript, 91.4 KB

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Cronin, O., Subedi, D., Forsyth, L., Goodman, K., Lewis, S. C., Keerie, C., Walker, A., Porteous, M., Cetnarskyj, R., Lakshminarayan, R., Selby, P., Hampson, G., Chandra, R., Ho, S., Tobias, J., Min, S. Y., McKenna, M., Crowley, R., Fraser, W. D., ... Ralston, S. H. (2020). Characteristics of early Paget's disease in SQSTM1 mutation carriers: Baseline analysis of the ZiPP study cohort. Journal of Bone and Mineral Research. Advance online publication. https://doi.org/10.1002/jbmr.4007

@article{f2a7ac55cf484e70bbb9086063bc6a04,

title = "Characteristics of early Paget's disease in SQSTM1 mutation carriers: Baseline analysis of the ZiPP study cohort",

abstract = "OBJECTIVES: Mutations in SQSTM1 are strongly associated with Paget's disease of bone (PDB) but little is known about the clinical characteristics of those with early disease.METHODS: Radionuclide bone scans, biochemical markers of bone turnover and clinical characteristics were analysed in SQSTM1 mutation carriers who took part in the Zoledronic acid in the Prevention of Paget's disease (ZiPP) study.RESULTS: We studied 222 individuals of whom 54.9% were female with average (± sem) age of 50.1± 0.6 years. Twelve SQSTM1 mutations were observed, including p.Pro392Leu which was present in 141/222 (63.5%) subjects. Bone scan examination revealed evidence of PDB in 20 subjects (9.0%) of which 9 (50%) had a single affected site. Participants with lesions were older than those without lesions but the difference was not significant (53.6 ± 9.1 vs. 49.8 ± 8.9, p=0.07). The mean age of participants with lesions was not significantly different from the age at which their parents were diagnosed with PDB (55 years vs. 59 years, p=0.25). All individuals with lesions were asymptomatic. Serum concentrations of total alkaline phosphatase (ALP) normalised to the upper limit of normal in each centre were higher in those with lesions (0.75 ± 0.69 vs 0.42 ± 0.29; p<0.0001). Similar findings were observed for other biochemical markers of bone turnover but the sensitivity of ALP and other markers in detecting lesions was poor.CONCLUSIONS: Asymptomatic PDB is present in about 9% of SQSTM1 mutation carriers by the fifth decade. Further follow up of this cohort will provide important information on the natural history of early PDB and its response to treatment. This article is protected by copyright. All rights reserved.",

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

year = "2020",

month = mar,

day = "16",

doi = "10.1002/jbmr.4007",

language = "English",

journal = "Journal of Bone and Mineral Research",

issn = "0884-0431",

publisher = "Wiley-Blackwell",

}

Cronin, O, Subedi, D, Forsyth, L, Goodman, K, Lewis, SC , Keerie, C, Walker, A, Porteous, M, Cetnarskyj, R, Lakshminarayan, R, Selby, P, Hampson, G, Chandra, R, Ho, S, Tobias, J, Min, SY, McKenna, M, Crowley, R, Fraser, WD, Tang, J, Gennari, L, Nuti, R, Brandi, M-L, Del Pino-Montes, J, Devogelaer, J-P, Durnez, A, Isaia, GC, Di Stefano, M, Rubio, JB, Guanabens, N, Seibel, M, Walsh, JP, Kotowicz, MA, Nicholson, GC, Duncan, EL, Major, G, Horne, A, Gilchrist, N & Ralston, SH 2020, 'Characteristics of early Paget's disease in SQSTM1 mutation carriers: Baseline analysis of the ZiPP study cohort', Journal of Bone and Mineral Research. https://doi.org/10.1002/jbmr.4007

TY - JOUR

T1 - Characteristics of early Paget's disease in SQSTM1 mutation carriers

T2 - Baseline analysis of the ZiPP study cohort

AU - Cronin, Owen

AU - Subedi, Deepak

AU - Forsyth, Laura

AU - Goodman, Kirsteen

AU - Lewis, Steff C

AU - Keerie, Catriona

AU - Walker, Allan

AU - Porteous, Mary

AU - Cetnarskyj, Roseanne

AU - Lakshminarayan, Ranganath

AU - Selby, Peter

AU - Hampson, Geeta

AU - Chandra, Rama

AU - Ho, Shu

AU - Tobias, Jon

AU - Min, Steven Young

AU - McKenna, Malachi

AU - Crowley, Rachel

AU - Fraser, William D

AU - Tang, Jonathan

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 - Rubio, Josep Blanch

AU - Guanabens, Nuria

AU - Seibel, Markus

AU - Walsh, John P

AU - Kotowicz, Mark A

AU - Nicholson, Geoffrey C

AU - Duncan, Emma L

AU - Major, Gabor

AU - Horne, Ann

AU - Gilchrist, Nigel

AU - Ralston, Stuart H

PY - 2020/3/16

Y1 - 2020/3/16

N2 - OBJECTIVES: Mutations in SQSTM1 are strongly associated with Paget's disease of bone (PDB) but little is known about the clinical characteristics of those with early disease.METHODS: Radionuclide bone scans, biochemical markers of bone turnover and clinical characteristics were analysed in SQSTM1 mutation carriers who took part in the Zoledronic acid in the Prevention of Paget's disease (ZiPP) study.RESULTS: We studied 222 individuals of whom 54.9% were female with average (± sem) age of 50.1± 0.6 years. Twelve SQSTM1 mutations were observed, including p.Pro392Leu which was present in 141/222 (63.5%) subjects. Bone scan examination revealed evidence of PDB in 20 subjects (9.0%) of which 9 (50%) had a single affected site. Participants with lesions were older than those without lesions but the difference was not significant (53.6 ± 9.1 vs. 49.8 ± 8.9, p=0.07). The mean age of participants with lesions was not significantly different from the age at which their parents were diagnosed with PDB (55 years vs. 59 years, p=0.25). All individuals with lesions were asymptomatic. Serum concentrations of total alkaline phosphatase (ALP) normalised to the upper limit of normal in each centre were higher in those with lesions (0.75 ± 0.69 vs 0.42 ± 0.29; p<0.0001). Similar findings were observed for other biochemical markers of bone turnover but the sensitivity of ALP and other markers in detecting lesions was poor.CONCLUSIONS: Asymptomatic PDB is present in about 9% of SQSTM1 mutation carriers by the fifth decade. Further follow up of this cohort will provide important information on the natural history of early PDB and its response to treatment. This article is protected by copyright. All rights reserved.

AB - OBJECTIVES: Mutations in SQSTM1 are strongly associated with Paget's disease of bone (PDB) but little is known about the clinical characteristics of those with early disease.METHODS: Radionuclide bone scans, biochemical markers of bone turnover and clinical characteristics were analysed in SQSTM1 mutation carriers who took part in the Zoledronic acid in the Prevention of Paget's disease (ZiPP) study.RESULTS: We studied 222 individuals of whom 54.9% were female with average (± sem) age of 50.1± 0.6 years. Twelve SQSTM1 mutations were observed, including p.Pro392Leu which was present in 141/222 (63.5%) subjects. Bone scan examination revealed evidence of PDB in 20 subjects (9.0%) of which 9 (50%) had a single affected site. Participants with lesions were older than those without lesions but the difference was not significant (53.6 ± 9.1 vs. 49.8 ± 8.9, p=0.07). The mean age of participants with lesions was not significantly different from the age at which their parents were diagnosed with PDB (55 years vs. 59 years, p=0.25). All individuals with lesions were asymptomatic. Serum concentrations of total alkaline phosphatase (ALP) normalised to the upper limit of normal in each centre were higher in those with lesions (0.75 ± 0.69 vs 0.42 ± 0.29; p<0.0001). Similar findings were observed for other biochemical markers of bone turnover but the sensitivity of ALP and other markers in detecting lesions was poor.CONCLUSIONS: Asymptomatic PDB is present in about 9% of SQSTM1 mutation carriers by the fifth decade. Further follow up of this cohort will provide important information on the natural history of early PDB and its response to treatment. This article is protected by copyright. All rights reserved.

U2 - 10.1002/jbmr.4007

DO - 10.1002/jbmr.4007

M3 - Article

C2 - 32176830

SN - 0884-0431

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

ER -

Characteristics of early Paget's disease in SQSTM1 mutation carriers: Baseline analysis of the ZiPP study cohort

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