Efficacy and Mechanism Evaluation (Jun 2024)
Prophylactic zoledronic acid therapy to prevent or modify Paget’s disease of bone progression in adults with SQSTM1 mutations: the ZiPP RCT
Abstract
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. Plain language summary Paget’s disease of bone causes bones to enlarge and become more fragile, potentially leading to pain, deformity, fractures, osteoarthritis and deafness. In normal clinical practice, Paget’s disease of bone is often diagnosed at a late stage during the course of the disease when bone damage is irreversible. Early diagnosis and treatment may be beneficial. Mutations in the SQSTM1 gene can cause Paget’s disease of bone to run in families and people with Paget’s disease of bone who carry these mutations have more severe and extensive disease with an earlier age at onset. In this study, genetic testing for SQSTM1 mutations was offered to 1307 people with a family history of Paget’s disease of bone with 750 individuals agreeing to be tested. Of these individuals, 350 (46.7%) were found to carry SQSTM1 mutations and were invited to take part in the trial; 222 people accepted and were enrolled into the study. They were randomly assigned to receive the drug zoledronic acid or a placebo. Both groups were followed for about 7 years. At the start of the study, 9.5% of participants already had Paget’s disease of bone lesions. Over time, two people on placebo developed new lesions compared to none on zoledronic acid. In the placebo group, eight people had poor outcomes such as new or worsening lesions versus none in the zoledronic acid group. Treatment with zoledronic acid made existing lesions disappear more often than placebo. One person on placebo required treatment with zoledronic acid as they developed Paget’s disease of bone-related symptoms. The study showed that it is feasible to identify people with early Paget’s disease of bone by genetic testing coupled with bone scan examination in those with a family history of Paget’s disease of bone. Treatment with zoledronic acid caused existing lesions to disappear more often than placebo. Genetic testing for SQSTM1 mutations coupled with bone scan examination and prophylactic zoledronic acid treatment may be beneficial in people with a family history of Paget’s disease of bone. Scientific summary Background In Paget’s disease of bone (PDB), the normal process of renewal and repair of the skeleton is abnormal, causing affected bones to enlarge and weaken, resulting in pain, deformity, fractures, secondary osteoarthritis and deafness. People with PDB often present when the disease at an advanced stage with irreversible bone damage. The main treatment option is bisphosphonates, which significantly reduces the increased bone turnover associated with PDB, as well as reducing the associated pain in some patients. However, bisphosphonates cannot reverse bone deformity, deafness or arthritis in PDB with the result that symptomatic benefits are often blunted in people with advanced disease. The most important susceptibility gene for PDB is SQSTM1. Mutations of this gene are observed in up to 40% of individuals with a family history of PDB and up to 15% of those who are unaware of a family history (Makaram NS, Ralston SH. Genetic determinants of Paget’s disease of bone. Curr Osteoporos Rep 2021;19:327–37). Carriers of SQSTM1 mutations have been shown to have more severe disease with an earlier age of onset than those who do not have such mutations. It has been estimated that about 80% of SQSTM1 carriers may develop PDB by the time they have reached their seventh decade [Morissette J, Laurin N, Brown JP. Sequestosome 1: mutation frequencies, haplotypes, and phenotypes in familial Paget’s disease of bone. J Bone Miner Res 2006;21(Suppl 2):38–44]. The zoledronic acid (ZA) to prevent the development of Paget’s disease [(zoledronic acid in the prevention of Paget’s disease (ZiPP)] trial was a double-blind, placebo-controlled randomised study aimed to determine if therapeutic intervention with a single infusion of 5 mg ZA would favourably alter the progression of PDB in people with a family history of PDB who test positive for SQSTM1 mutations, but who had not yet been diagnosed with PDB. Objectives The primary objective was to determine if ZA could prevent the development of bone lesions with the characteristics of PDB in people who carry SQSTM1 mutations. Additional objectives were to determine if ZA could modify the appearance of existing PDB lesions; modify biochemical markers of bone turnover; modify quality of life, bone pain, anxiety and depression; or modify the risk of complications related to the development of PDB. Methods The ZiPP trial was a randomised, double-blind placebo-controlled trial conducted in 25 centres from 7 countries worldwide. A genetic screening programme was offered to 1307 people with a family history of PDB and 750 agreed to be tested. This resulted in the identification of 350 individuals who were carriers of SQSTM1 mutations but who were not known to have developed PDB. Of these, 222 (63.4%) consented to participate in the study. At the baseline visit, a radionuclide bone scan was performed to detect the presence of bone lesions with the characteristics of PDB; blood samples were taken for analysis of biochemical markers of bone turnover and questionnaires were completed to assess pain, health-related quality of life and anxiety or depression. Participants were then randomly allocated to receive a single infusion of the bisphosphonate ZA 5 mg intravenously or an identical placebo. Both groups were followed up annually where blood samples and questionnaires were repeated. Adverse events (AEs) were recorded on a continuous basis. At the end of study, the bone scan was repeated, bloods were taken for assessment of biochemical markers and questionnaires were repeated. Results At baseline, 21/222 individuals (9.5%) already had evidence of PDB on bone scans. Two out of 90 individuals (2.2%) allocated to placebo developed new bone lesions compared with 0 out of 90 (0%) allocated to ZA {odds ratio [OR] = [OR 0.41, 95% confidence interval (CI) 0.00 to 3.43; p = 0.25]}. Eight participants in the placebo group had a poor outcome (lesions that were new, unchanged or progressing) compared with none in the ZA group (OR 0.08, 95% CI 0.00 to 0.42; p = 0.003). In the ZA group, 13/15 lesions present at the start had disappeared compared with 1/29 lesions that disappeared in the placebo group (p < 0.0001, between groups). One participant allocated to placebo required treatment with ZA due to the emergence of symptoms related to PDB. Biochemical markers of bone remodelling were significantly suppressed by ZA. For plasma type I collagen C-terminal telopeptide (CTX), which is a marker of bone resorption, the estimated least squares mean [95% CI] treatment difference taking all timepoints into account was −0.09 [−0.12 to −0.07] (p < 0.0001) in favour of ZA. For plasma procollagen type I amino-terminal propeptide, which is a marker of bone formation, the estimated treatment difference was −16.32 [−22.05 to −10.59] (p < 0.0001) also in favour of the ZA group. Finally, for serum bone-specific alkaline phosphatase (BAP), another marker of bone formation, the estimated treatment effect was −1.68 [−2.59 to −0.78]; p = 0.0003 in favour of ZA. There was no significant difference between the groups in quality of life, bodily pain, or anxiety and depression, and no difference between the groups in AEs or serious adverse events (SAEs). Limitations The study had some limitations. First, 9.5% of participants already had Paget’s disease, reducing the power to detect treatment effects. Second, only two participants developed new lesions compared to the 15% expected. The small number of events meant that the study was not powered to meet the primary outcome. In addition, the small number of events meant that the study was unable to analyse the data by logistic regression to adjust for covariates or family clustering as was initially planned. This estimate was based on limited cross-sectional data on the increasing PDB incidence with age. Conclusion The trial has shown that genetic testing for SQSTM1 mutations coupled with bone scan examination can detect early PDB in those with a family history of the disorder. It also shows that ZA treatment can favourably modify the evolution of PDB in this participant group. The offer of genetic testing for SQSTM1 coupled with bone scan examination and targeted intervention with ZA can modify the evolution of PDB in those with a family history of the disorder. Further research is required to evaluate the clinical and health-economic benefits of this approach in the longer term. Further research with an extended follow-up in the ZiPP- long term extension (LTE) study is in progress, and it will provide valuable information on the duration of the effects of a single infusion of ZA on those with existing lesions and the development of new lesions in both treatment groups. Although this was an experimental medicine study, it will now be important to consider a health-economic analysis to try to model the effects of genetic testing, bone scanning and ZA treatment in this participant group to evaluate the likelihood of 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.
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