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

Abstract

IntroductionPaget’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.MethodsWe randomised 222 individuals at increased risk of PDB because of pathogenicSQSTM1variants 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.ResultsThe 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.ConclusionsGenetic testing for pathogenicSQSTM1variants coupled with intervention with ZA is well tolerated and has favourable effects on the progression of early PDB.Trial registration numberISRCTN11616770.

Diagnosis and treatment of Paget’s disease of bone: position paper from the Italian Society of Osteoporosis, Mineral Metabolism and Skeletal Diseases (SIOMMMS)

“…Indeed, in a recent screening of baseline clinical, radiological and bone scan characteristics of 222 apparently unaffected carriers of SQSTM1 mutations (from known PDB families) who took part in the Zoledronic acid in the Prevention of Paget’s disease (ZiPP) study, asymptomatic PDB was confirmed in about 9% of cases [ 52 ]. Importantly, in the very recent report of that trial, after a median duration of 84 months, zoledronate-treated subjects did not develop any new pagetic lesion compared to placebo [ 68 ]. An improvement of existing lesions (completely disappearing on bone scan in 87% of cases) was also demonstrated in zoledronate-treated subjects versus placebo.…”

The Decline of Paget’s Disease of Bone and Domestic Coal Use—A Hypothesis

“…In Lancaster in the north-west of England the prevalence of PDB has fallen by an order of magnitude—from 8 to 0.8%—in 40 years [ 21 ]. In the ZiPP study of SQSTM1 mutation carriers, the rate at which PDB had developed in the placebo group by the end of the study (2021) was only one eighth that anticipated when the study was registered 13 years earlier [ 22 ]. So there is little question that the nature of Paget’s disease has changed from its apparent peak in the late nineteenth and early twentieth century.…”