Tan 2017.

Methods	Interventional extension study including participants who complete a previous RCT (Langston 2010). The bisphosphonate of first choice in the intensive treatment arm was different from the original trial. Randomisation ratio: 1:1 (symptomatic treatment: intensive treatment). Superiority design
Participants	Diagnostic criteria: participants with Paget's disease of bone confirmed by plain radiology of at least one skeletal site according standard criteria from UK guidelines (Selby 2002) Inclusion criteria: Participants who completed the PRISM trial (Langston 2010). Exclusion criteria: No specific exclusion criteria were applied on the basis of treatment history, baseline alkaline phosphatase or co‐existing diseases. Number invited to participate: 2110 Number enrolled: 502 Number analysed: 404 (76 years, 54% male, 62% symptomatic, 91% previously treated with bisphosphonates for Paget's disease, 70% had normal alkaline phosphatase at baseline)
Interventions	Two parallel treatment groups; symptomatic vs. intensive treatment. Symptomatic treatment: Philosophy; treat bone pain, not alkaline phosphatase. No treatment was administered for participants without symptoms referable to Paget's disease of bone. For participants with pain caused by Paget's disease of bone, the first‐line treatment was analgesics and nonsteroidal anti‐inflammatory drugs. If there was an inadequate response, participants could be treated with: tiludronate (400 mg daily for 3 months), etidronate (400 mg daily for 3 to 6 months) or calcitonin ( subcutaneously administered 50 to 100 units daily for 3 months). Pamidronate (initial 30 g dose and further infusions of 30 mg until a response occurred to a maximum dose of 180 mg), and Risedronate (30 mg daily for 2 months) could be used if there was inadequate response to previous treatment. Zoledronate (5 mg as a single infusion) could be used if there was inadequate response to previous treatment. Intensive treatment: Philosophy; maintain normal alkaline phosphatase. No treatment was administered for participants with normal alkaline phosphatase. For participants with elevated alkaline phosphatase zoledronate 5 mg intravenously was chosen as first‐line treatment. Risedronate (30 mg daily for 2 months), pamidronate (3 intravenous infusion of 60 mg, total dose 180 mg), tiludronate (400 mg daily for 3 months), etidronate (400 mg daily for 3 to 6 months) or calcitonin (subcutaneously administered 50 to 100 units daily for 3 months) could also be used. The aim was to restore and maintain alkaline phosphatase levels within the normal range; If there was an inadequate response, participants could be re‐treated. Co‐interventions: Analgesics and nonsteroidal anti‐inflammatory drugs
Outcomes	Primary outcome: radiologically‐confirmed clinical fracture. Secondary outcomes: adverse events related to use of bisphosphonates; need for orthopaedic surgery; change in quality of life measures (assessed using SF‐36) and mean percentage change from baseline in serum total alkaline phosphatase activity (alkaline phosphatase values were normalised to the upper limit of the reference range for each centre, which was set to a level of 1.0). Time points for measurement: Data on fractures, orthopaedic procedures and serious adverse events were collected on a continuous basis. Laboratory data, quality of life, bone pain and adverse events (based on participant diaries) data were measured annually. How were the outcomes measured: prospectively
Setting and date	30 secondary referral centres in the UK. Period the study was conducted: January 2007 to January 2012
Follow up period	3 years
Publication details and funding source	Language of publication: English. Publication status: Abstract. Funding source: The study was supported by grants from the Arthritis Research Campaign UK (Ref. 13627) and the National Association for Relief of Paget’s Disease. Declarations of interest among primary researchers: SHR reported receiving consulting fees on behalf of his institution from Novartis and Merck and a research grant to his institution from Amgen. WDF reported receiving consultancy fees from Siemens, Becton Dickinson and Roche. PLS reported receiving consultancy fees from Internis. All other authors stated they had no conflicts of interest.
Notes	The study was described by the authors as a "pragmatic randomised controlled trial designed to compare the effects of two management strategies". The study was not blinded
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "At the end of PRISM, patients were asked if they wanted to continue in the study for a further three years". Comment: The participants included in this trial had participated in a previous trial (Langston 2010). The risk of bias assessment should be the same as for the previous trial. However, as only participants who voluntarily agreed to continue in the study were included, it is difficult to verify if the balance among the trial groups created in the original trial by randomisation was kept in this extension study. At baseline serum alkaline phosphatase levels were lower in the intensive versus symptomatic group reflecting the fact that these participants already had been subjected to intensive treatment
Allocation concealment (selection bias)	High risk	Comment: The participants included in this trial had participated in a previous trial (Langston 2010). The risk of bias assessment is the same as for the previous trial
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: The study was not blinded. The main outcome (fractures) was unlikely to be influenced by lack of blinding. The risk of bias was high for quality of life, adverse events or bone pain, but low for other secondary endpoints as orthopaedic procedures or alkaline phosphatase concentrations
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Patient‐reported fractures and orthopaedic procedures were validated against medical records and x‐ray reports at participating centres by assessors blinded to treatment allocation"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: Although a similar proportion of participants were deceased, withdrew from the study, declined to participate or were lost to follow up in each group (41/232 (18%) in the symptomatic versus 57/270 (21%) in the intensive group) at 3 years time, the proportion of missing outcomes compared with observed event risk is enough to induce clinically relevant bias in intervention effect estimate (fracture). However, the assessment of attrition bias is not assessed as high but low as, according to authors, the study was an event driven trial, with fracture as the primary endpoint. Data on all fracture events were available even in subjects who had withdrawn from the study
Selective reporting (reporting bias)	Low risk	Study protocol available. There was a prespecified record of the studies outcomes and all of them were included in published manuscript
Other bias	Unclear risk	The study design permitted attending clinicians to choose between different drugs within a specified treatment strategy. Evidence that the attending clinicians adhered to this strategy was confirmed by the observed difference in alkaline phosphatase levels between groups