Zoledronate in the Prevention of Paget’s disease (ZiPP)

The ZiPP study was a clinical research study run by the Edinburgh Clinical Trials Unit. The team at the Paget's Association were part of the Steering Committee.

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

The study
This was a multicentre, international 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 take part. A radionuclide bone scan was carried out; 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 and adverse events were recorded. At the end of the study, the bone scan was repeated, along with biochemical markers and the questionnaires. 27 secondary care referral centres for bone disease took part, in 7 countries. Participants were randomly allocated to receive a single infusion of the bisphosphonate zoledronic acid 5 mg or an identical placebo.

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 Paget'sdisease between the baseline visit and the final end-of-study visit. The secondary outcomes included the number of new Pagetic bone lesions on radionuclide bone scans, change in the activity of existing 

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.

The researchers concluded that 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, 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.

Reference

Phillips J, Subedi D, Lewis SC, Keerie C, Ralston SH. Prophylactic zoledronic acid therapy to prevent or modify Paget’s disease of bone progression in adults with SQSTM1 mutations: the ZiPP RCT. Efficacy Mech Eval 2024;11(10). https://doi.org/10.3310/FTKC20...

Aug 2026