Pagets disease of bone (PDB) is a common disorder with a strong genetic component. The most important susceptibility gene is Q1STM1. Mutations of this gene are found in about 40% of patients with familial and 10% of those with sporadic PDB but there is limited information on the early characteristics of disease evolution in Q1STM1 mutation carriers Here we report on the baseline clinical characteristics of participants of the ZIPP study - a multinational randomised trial of genetic testing and targeted intervention with Zoledronic acid in asymptomatic subjects who carry Q1STM1 mutations. The study group comprised 203 Q1STM1 mutation positive subjects of mean (± SD) age 49.2±9.0 years of whom 110 (54.4%) were female. The most common mutation was P392L (63.5%) followed by M404V (12.3%), G425R (9.9%), A390X (3.9%), G411S (3.4%), Glu396X (1.5%), Thr350GlnfsX28 (1.5%), Gln371X (1%), F406V (1%), K378X (1%), E396X (0.5%) and l424S (0.5%). Analysis of radionuclide bone scan images at baseline revealed abnormalities that were thought to represent early PDB-like lesions in 31 subjects (15.2%). The commonest sites were the spine (48%), pelvis (35%), femur (12%) and tibia (6.4%). About 30% of subjects had multiple lesions. All subjects were asymptomatic. Serum total alkaline phosphatase (ALP) concentrations were elevated in 10 subjects (5%). Subjects with PDB-like lesions were marginally older than those without lesions 51.1±9.4 vs. 49.2±8.9 and lesions were significantly more common in men (20.6% vs. 10.9% (p=0.02). Elevated ALP concentrations were found in 16% of subjects with lesions and 3% of subjects without lesions (p=0.002). There was no association between Q1STM1 mutation type and the presence of lesions. This study demonstrates that by the age of 50 about 15% of Q1STM1 mutation carriers have asymptomatic PDB-like bone lesions. Lesions occur more commonly in men, which is consistent with the fact that PDB affects men more frequently than women. The study confirms that PDB is a clinically silent disease in its early stages and shows that measurements of total ALP are not a sensitive means of detecting early lesions. Further follow up of this cohort will provide a unique insight into the evolution of PDB with age and into the effects of zoledronic acid in modifying the natural history of this condition.
Disclosure: Consultancy to institution for Merck and Novartis. Research funding from Novartis, Amgen, Eli Lilly, Arthritis Research UK and Medical Research Council.