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

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

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

Key Messages What is already known about this subject? • Paget’s Disease of Bone (PDB) frequently presents at an advanced stage with complications secondary to irreversible skeletal damage. Clinical outcome might be improved by earlier diagnosis and prophylactic treatment. • Genetic factors are important in the pathogenesis of PDB and individuals who carry pathogenic variants in SQSTM1 have more severe disease with an earlier age at onset than those who do not. What does this study add? • Genetic testing for pathogenic SQSTM1 variants in people with a family history of PDB coupled with radionuclide bone scan examination in those that test positive can be used to detect the disease at an early stage. • Prophylactic treatment with zoledronic acid (ZA) in SQSTM1 positive individuals favourably affects the development and progression of early Paget’s disease. How might this impact on clinical practice? • This study supports the introduction of a program of genetic testing for people with a family history of PDB coupled with the offer of prophylactic ZA treatment in carriers of pathogenic SQSTM1 variants