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.