Prophylactic zoledronic acid therapy to prevent or modify Paget’s disease of bone progression in adults with SQSTM1 mutations: the ZiPP RCT
Authors: Phillips Jonathan , Subedi Deepak , Lewis Steff C , Keerie Catriona , Ralston Stuart H 
Published: October 2023

Background
Paget’s disease of bone is characterised by focal abnormalities of bone turnover resulting in various complications. It often presents at an advanced stage with irreversible bone damage. At this point, the symptomatic benefits of treatment are blunted. Paget’s disease of bone has a strong genetic component and the most important susceptibility gene is SQSTM1. Carriers of SQSTM1 mutations have more severe disease with an earlier age of onset than non-carriers and about 80% develop Paget’s disease of bone by the seventh decade.

Objectives
The primary objective was to determine if zoledronic acid could prevent new Paget’s disease of bone-like bone lesions in SQSTM1 mutation carriers. Secondary objectives were to assess if zoledronic acid could: modify existing Paget’s disease of bone lesions, markers of bone turnover, quality of life, bone pain, anxiety, depression or the risk of complications.

Design
This was a multicentre, double-blind placebo-controlled trial. Genetic screening of the SQSTM1 gene was offered to people with a family history of Paget’s disease of bone, identifying 222 mutation carriers who consented to participate. At baseline, a radionuclide bone scan was performed; biochemical markers of bone turnover were measured and questionnaires on pain, quality of life and mental health were completed. Participants completed annual biochemical markers measurements and questionnaires. Adverse events were recorded on a continuous basis. At the end of study, the bone scan was repeated, along with biochemical markers and questionnaires.

Setting
This was a multicentre trial that was conducted at 27 secondary care referral centres for bone disease in 7 countries. All the visits were conducted within a secondary healthcare setting.

Participants Interventions
Participants were randomly allocated to receive a single infusion of the bisphosphonate zoledronic acid 5 mg or an identical placebo.

Main outcome measures
The study’s primary outcome measure was defined as the total number of participants who developed new bone lesions on radionuclide bone scans with the characteristics of PDB between the baseline visit and the final end-of-study visit. The secondary outcomes included the number of new PDB bone lesions on radionuclide bone scans, change in the activity of existing PDB bone lesions at the end of study assessed by radionuclide scans; changes in plasma type I collagen C-telopeptides (CTX); plasma procollagen type I amino-terminal propeptide (PINP); serum bone-specific alkaline phosphatase (BAP); quality of life assessed by SF-36, BPI, HADS questionnaires; the presence and severity of localized bone pain assessed by the BPI pain manikin; and the development of PDB-related skeletal events (PDRSE) in SQSTM1 mutation carriers including new lesions, complications (fractures, deformity), or the need for treatment of PDB.

Methods
This was a multicentre, double-blind placebo-controlled trial. Genetic screening of the SQSTM1 gene was offered to people with a family history of Paget’s disease of bone, identifying 222 mutation carriers who consented to participate. At baseline, a radionuclide bone scan was performed; biochemical markers of bone turnover were measured and questionnaires on pain, quality of life and mental health were completed. Participants were randomly allocated to receive a single infusion of the bisphosphonate zoledronic acid 5 mg or an identical placebo. Participants completed annual biochemical markers measurements and questionnaires. Adverse events were recorded on a continuous basis. At the end of study, the bone scan was repeated, along with biochemical markers and questionnaires.

Results
At baseline, 21/222 individuals (9.5%) had evidence of Paget’s disease of bone on bone scans. In the placebo group, 2/90 individuals (2.2%) developed new bone lesions compared with 0/90 (0%) in the zoledronic acid group (odds ratio 0.41, 95% confidence interval 0.00 to 3.43; p = 0.25). Eight participants in the placebo group had a poor outcome (new/unchanged/progressing lesions) compared with none in the zoledronic acid group (odds ratio 0.08, 95% confidence interval 0.00 to 0.42; p = 0.003). With placebo, 1/29 (3.4%) lesions disappeared compared with 13/15 (86.6%) with zoledronic acid (p < 0.0001). One participant allocated to placebo required treatment with zoledronic acid due to a complication of Paget’s disease of bone. Significant reductions were observed for serum C-terminal telopeptide (p < 0.0001), bone-specific alkaline phosphatase (p = 0.0003) and N-terminal propeptide of type I procollagen (p < 0.0001) in the zoledronic acid group compared with placebo. There was no significant difference between groups in quality of life, pain, anxiety or depression.

Conclusion
Genetic testing for SQSTM1 mutations coupled with bone scan examination can detect early Paget’s disease of bone in those with a family history of the disorder and zoledronic acid treatment can favourably modify its evolution.
The study had some limitations. First, 9.5% of participants already had Paget’s disease of bone, reducing power. Second, only two participants developed new lesions compared to the 15% expected. The small number of events meant the study was underpowered for the primary outcome and we were unable to adjust analyses for co-variates or family clustering.
An extended follow-up in the zoledronic acid in the prevention of Paget’s disease – long-term extension study is in progress and will provide valuable information on the duration of effects of a single zoledronic acid infusion. It will be important to consider a health economic analysis to model the effects of genetic testing, scanning and zoledronic acid treatment, to evaluate long-term clinical and symptomatic benefits.

Study registration
Current Controlled Trials ISRCTN11616770.

Funding
This award was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council (MRC) and National Institute for Health and Care Research (NIHR) partnership. This is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 10. See the NIHR Funding and Awards website for further award information.