Methods

RCT. Randomisation ratio: 9 (placebo): 7 (etidronate 1 mg/kg/day): 7 (etidronate 2.5 mg/kg/day): 9 (etidronate 5 mg/kg/day): 8 (etidronate 10 mg/kg/day): 7 (etidronate 20 mg/kg/day).

Superiority design

Participants

Diagnostic criteria: x‐ray evidence of Paget's disease of bone.

Inclusion criteria: Pain at one or more sites of Paget's bone involvement and elevated serum alkaline phosphatase or urinary hydroxyproline at least twice the upper limit of normal (ULN) range.

Exclusion criteria: not stated.

Number screened: not stated.

Number randomised: 50.

Number analysed: 47 (65 years, 60% male; percentages monostotic, symptomatic and previously treated for Paget's disease of bone not stated)

Interventions

6 parallel treatment groups; placebo and etidronate in 5 different doses (1 mg, 2.5 mg, 5 mg, 10 mg and 20 mg/kg/day).

Co‐interventions: not stated

Outcomes

Outcomes reported in abstract:

• change in bone pain (recorded as mild, moderate or severe);

• adverse events related to use of bisphosphonates;

• withdrawal due to adverse events;

• radiologically‐confirmed clinical fracture; and

• mean percentage change from baseline in serum total alkaline phosphatase activity (measured using thymolphthalein monophosphate method).

Time points for measurement: 6 months.

How were the outcomes measured: prospectively

Setting and date

One hospital bone unit (Miami, FL, USA).

Period when the study was conducted: Not stated

Follow up period

6 months

Publication details and funding source

Language of publication: English.
Publication status: peer‐reviewed journal; full article

Funding source: Supported in part by the General Clinical Research Center and a grant from the National Institute of Health (5MO1‐RR‐261‐08). Etidronate was supplied by the Procter and Gamble Company, Cincinnati, OH, USA

Declarations of interest among primary researchers: Not stated

Notes

Etidronate groups data were pooled for meta‐analysis

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

There were no data about how participants were selected. The authors did not use the term 'randomization', but the study was double‐blinded, so the study design should have had some way of randomising participants to administer treatment. However, the risk of bias should be likely high because no information was provided for the clinical characteristics of groups before starting the study (gender, age…) and the data on mean alkaline phosphatase or urinary hydroxyproline are clearly different at the start of the study for all groups

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "double‐blind study".
Comment: Probably done.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quote: "Scans were coded and read blind for qualitative change by at least two observers".

Comment: Outcome assessment was blinded for scans, but there was insufficient information to permit judgement about other outcomes

Incomplete outcome data (attrition bias)
All outcomes

High risk

Data from the original manuscript (Altman 1973) did not agree with data in the extension study (Khairi 1974).

Altman 1973: "Fifty patients entered the study".

Khairi 1974: "Fifty‐four patients started in this study".

Numbers of participants included in the treatment groups differed for Altman 1973 and Khairi 1974. In Altman 1973 23 participants were randomised to placebo plus 1 mg/kg and 2.5 mg/kg dose groups; this number was 24 in Khairi 1974. Altman 1973 reported randomising 9, 8 and 7 participants respectively to 5 mg/kg, 10 mg/kg and 10 mg/kg groups; in Khairi 1974 8, 10 and 8 participants were reported to have been randomised to these respective treatment arms

Selective reporting (reporting bias)

Unclear risk

Insufficient information to permit judgement. Methods and results sections were consistent. We did not have access to a trial register record or study protocol to know if there was a prespecified record of the studies outcomes

Other bias

Unclear risk

There were no data on exposure to co‐interventions other than bisphosphonates. No other risks of bias found, but reporting was insufficient to permit judgement.

Methods

RCT. Randomisation ratio: 1:2 (pamidronate: olpadronate).

Superiority design

Participants

Diagnostic criteria: Not stated.

Inclusion criteria: active Paget's disease of bone despite previous therapies.

Exclusion criteria: not stated.

Number screened: not stated.

Number randomised: 27.

Number analysed: 21 (age and sex not stated; percentages monostotic, symptomatic and previously treated for Paget's disease of bone were not stated)

Interventions

Two parallel treatment groups; pamidronate 400 mg/day for 4 months vs. olpadronate 200 mg/day for 12 days.

Co‐interventions: Not reported

Outcomes

Outcomes reported in abstract

Primary endpoint: Mean percentage change from baseline in serum total alkaline phosphatase activity.

Secondary endpoints: Number of participants who experienced adverse events related to use of bisphosphonates.

Time points for measurement: 6 months.

How were the outcomes were measured: Insufficient information. Likely prospectively

Setting and date

Multicentre; Argentina.

Period when the study was conducted: Not stated

Follow up period

6 months

Publication details and funding source

Language of publication: English.
Publication status: conference abstracts only.

Funding source: Not stated.

Declarations of interest among primary researchers: Not stated

Notes

Data only from abstracts

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "randomized in a 1:2 schedule." Randomisation method not reported

Allocation concealment (selection bias)

Unclear risk

Randomisation method not reported

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Both formulations were double dummy with placebos"

Comment: Probably done.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Insufficient information to permit judgement. Only an abstract of the trials was published. Many data were lacking; there were no data on attrition, exclusions or adverse events

Selective reporting (reporting bias)

Unclear risk

Insufficient reporting to permit judgement. Methods and results sections were poorly described. It was not possible to assess if they were consistent. We did not have access to a trial register record or study protocol to know if there was a prespecified record of the studies outcomes

Other bias

Unclear risk

There were no data on exposure to co‐interventions other than bisphosphonates. No other risks of bias found, but reporting was insufficient to permit judgement.

Methods

RCT. Randomisation ratio: 1:1:1:1:1 (placebo: zoledronate 50 µg: 100 µg; 200 µg; 400 µg)

Superiority design

Participants

Diagnostic criteria: x‐ray evidence of Paget's disease of bone

Inclusion criteria: Paget's disease of bone and serum alkaline phosphatase concentrations at least twice the ULN

Exclusion criteria: Treatment with bisphosphonates in the previous 6 months or calcitonin or plicamycin in the previous 3 months. Creatinine clearance < 60 mL/min. Abnormal liver function

Number screened: not stated

Number randomised: 176

Number analysed: 172 (71 years, 61% male; percentages monostotic, symptomatic or previously treated for Paget's disease of bone were not stated)

Interventions

5 parallel treatment groups; placebo and zoledronate in 4 doses (50 µg, 100 µg, 200 µg and 400 µg in a single intravenous infusion)

Co‐interventions: Not reported

Outcomes

Outcomes reported in abstract

Primary endpoint: Mean percentage change from baseline in serum total alkaline phosphatase activity

Secondary endpoints: Numbers of participants who experienced adverse events related to use of bisphosphonates

Time points for measurement: Baseline, 5 days, 10 days, 30 days, 45 days, 60 days and 90 days.

How were the outcomes measured: prospectively

Setting and date

20 sites in USA and UK.

Period when the study was conducted: Not stated

Follow up period

3 months

Publication details and funding source

Language of publication: English.
Publication status: peer‐reviewed journal; full article.

Funding source: Funding source not reported in the manuscript, but one author, P Richardson, indicated "Ciba Pharmaceuticals" (abstract) and "Clinical Research, Novartis Pharmaceuticals, East Hanover, NJ, USA" (primary reference) affiliations

Declarations of interest among primary researchers: Not stated

Notes

Zoledronate groups data were pooled for meta‐analysis

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "The patients were randomized in a double‐blind manner". The allocation method was not described

Allocation concealment (selection bias)

Unclear risk

The allocation method was not described

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Randomized in a double blind manner".

Comment: Probably done.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement. The risk of bias was likely to be low for serum data because assays for bone‐specific alkaline phosphatase, urinary calcium, creatinine, hydroxyproline, pyridinoline and deoxypiridinoline were conducted in a central laboratory (Nichols Institute, San Juan Capistrano, CA, USA)

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "All efficacy analyses were based on all randomised patients who had at least one post baseline measurement (intention‐to‐treat analysis). Four of the 176 patients did not complete all post baseline evaluations".

Comment: Attrition data were provided

Selective reporting (reporting bias)

Unclear risk

Insufficient information to permit judgement. Methods and results sections were consistent. We did not have access to a trial register record or study protocol to know if there was a prespecified record of the studies outcomes

Other bias

Unclear risk

There were no data on exposure to co‐interventions other than bisphosphonates. No other risks of bias found, but reporting was insufficient to permit judgement

Methods

RCT. Randomisation ratio: 12 (placebo): 7 (etidronate 2.5 mg/kg/day): 8 (etidronate 5 mg/kg/day): 11 (etidronate 10 mg/kg/day): 10 (etidronate 20 mg/kg/day).

Superiority design

Participants

Diagnostic criteria: x‐ray evidence of Paget's disease of bone.

Inclusion criteria: symptoms referable to the disorder, elevation of serum alkaline phosphatase and urinary hydroxyproline (with at least twice the normal value of one these indices).

Exclusion criteria: No co‐existing condition that would complicate the interpretation of therapeutic results. No other specific therapy for Paget's disease for at least 6 months before entry into the study.

Number screened: not stated.

Number randomised: 48.

Number analysed: 48 (age not stated, 58% male; percentages monostotic, symptomatic or previously treated for Paget's disease of bone were not stated)

Interventions

5 parallel treatment groups; placebo, and etidronate in 4 doses (2.5 mg, 5 mg, 10 mg and 20 mg/kg/day).

Co‐interventions: Not reported

Outcomes

Outcomes reported in abstract

Primary endpoint: mean percentage change from baseline in serum total alkaline phosphatase activity.

Secondary endpoints: change in bone pain (assessment tool used not reported); radiologically‐confirmed clinical fracture.

Time points for measurement: Baseline, 1 month, 2 months, 3 months, 4.5 months, 6 months.

How were the outcomes measured: prospectively

Setting and date

Participants admitted to 4 New York City Hospitals.

Period when the study was conducted: Not stated

Follow up period

6 months

Publication details and funding source

Language of publication: English.
Publication status: peer‐reviewed journal; full article.

Funding source: Supported by National Institute of Health grants (MO1.RR00645, 5.MO1‐RR‐96, AM‐09579, TIAM‐05397 and TIAM‐05531). Etidronate was supplied by the Procter and Gamble Company, Cincinnati, OH, USA.

Declarations of interest among primary researchers: Not stated

Notes

Etidronate groups data were pooled for meta‐analysis.

Data from 27 additional participants treated with etidronate in a non‐blinded, non‐randomised basis were included in the manuscript

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "each patient… was assigned randomly"
Comment: Randomisation method was not reported

Allocation concealment (selection bias)

Unclear risk

Randomisation method was not reported

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "for all the patients in treatment group A neither the investigator nor the patient knew the identity of the treatment".

Comment: Probably done.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information provided to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No losses to follow‐up reported. However, it was not clear how many participants were included

Selective reporting (reporting bias)

High risk

We did not have access to a trial register record or study protocol to know if there was a prespecified record of the studies outcomes.

Likely selective reporting risk is high due to vague data on adverse events. There are no specific number of patients but only sentences as "some patients… showed a rise in serum phosphate"

Other bias

Unclear risk

There were no data on exposure to co‐interventions other than bisphosphonates. No other risks of bias found, but reporting was insufficient to permit judgement

Methods

RCT. Randomisation ratio: 1:1:1:1 (placebo: tiludronate 200 mg, 400 mg, 600 mg).

Superiority design

Participants

Diagnostic criteria: Paget's disease confirmed by scintigraphy or radiography or both

Inclusion criteria: Age ≥ 18 years; serum alkaline phosphate concentration at least twice the ULN

Exclusion criteria:

• prior treatment with bisphosphonates other than etidronate within the past 2 years;

• treatment with etidronate, mithramycin or calcitonin within 6 months;

• prior treatment at any time if the current serum alkaline phosphatase concentration was < 30% above the lowest concentration then achieved;

• recent fracture or confinement to bed;

• current peptic ulceration;

• clinically significant liver, kidney or haematological disorder;

• pre‐menopausal women;

• malignant neoplasia within the previous 5 years or breast malignancy within the previous 10 years; or

• recent change in dose of hormone replacement therapy, vitamin D or corticosteroids.

Number screened: not stated.

Number randomised: 112.

Number analysed: 112 (70 years, 54% male, 30% monostotic, 63% symptomatic, percentage previously treated for Paget's disease of bone not stated)

Interventions

4 parallel treatment groups; placebo and tiludronate in 3 doses (200 mg, 400 mg, 600 mg/day) for 12 weeks.

Co‐interventions: Not reported

Outcomes

Outcomes reported in abstract

Primary endpoint: Mean percentage change from baseline in serum total alkaline phosphatase activity. Treatment success was defined as 50% reduction in serum alkaline phosphatase concentration compared with baseline after 12 weeks' treatment. (Concentration decreased by 25% or less compared with week 0 reading was defined as resistant).

Secondary endpoints

• change in bone pain (measured using VAS. Scale ranged from no pain to agonising pain);

• adverse events related to use of bisphosphonates;

• radiologically‐confirmed clinical fracture;

• participants who required orthopaedic surgery;

• withdrawal due to adverse events; and

• relapse due to recurrence of bone pain.

Time points for measurement: Baseline, 2 weeks, 8 weeks, 12 weeks, 24 weeks.

How were the outcomes measured: prospectively

Setting and date

16 hospitals in the UK.

Period when the study was conducted: Not stated

Follow up period

6 months. An additional follow‐up to assess the need for re‐treatment was carried out 18 months after the last participant had completed the 6 month trial. Follow‐up was via a postal questionnaire with participants who had completed at least 11 weeks of treatment

Publication details and funding source

Language of publication: English.
Publication status: peer‐reviewed journal; full article.

Funding source: Research supported by Sanofi Winthrop Ltd.

Declarations of interest among primary researchers: Not stated

Notes

Tiludronate groups data were pooled for meta‐analysis

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Patients were allocated sequential study numbers and randomly assigned to one of the four treatment groups".
Comment: Likely there was a central allocation because 16 hospitals recruited participants in the UK

Allocation concealment (selection bias)

Unclear risk

Insufficient information provided to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "double‐blind randomised study".

Comment: Probably done.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information provided to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "Data were analysed on an 'intention to treat' basis".

Comment: Reasons for missing outcome data (lost to follow‐up and withdrawals) are reported

Selective reporting (reporting bias)

Unclear risk

Insufficient information to permit judgement. We did not have access to a trial register record or study protocol to know if there was a prespecified record of the studies outcomes.

Quote: "A visual analogue scale was used for patients to assess their Pagetic pain".

Comment: Although stated that "there were no significant differences between any of the treatment groups" data for pain assessment were only provided for placebo and tiludronate higher dose groups

Other bias

Unclear risk

There were no data on exposure to co‐interventions other than bisphosphonates. No other risks of bias found, but reporting was insufficient to permit judgement

Methods

RCT. Randomisation ratio: 1:1 (symptomatic treatment: intensive treatment).

Superiority design

Participants

Diagnostic criteria: diagnosis confirmed on plain radiograph of at least one skeletal site according standard criteria from UK guidelines (Selby 2002).

Inclusion criteria: Paget's disease of bone and life expectancy > 1 year.

Exclusion criteria: No specific exclusion criteria were applied on the basis of treatment history, baseline alkaline phosphatase or co‐existing diseases.

Number assessed: 2110.

Number randomised: 1331.

Number analysed: 1159 (74 years, 51% male, 35% monostotic, 69% symptomatic, 90% previously treated with bisphosphonates for Paget's disease, 52% 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, first‐line treatments were 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 (an initial dose of 30 mg 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.

Intensive treatment: Philosophy; maintain normal alkaline phosphatase.

• No treatment was administered for participants with normal alkaline phosphatase;

• • For participants with elevated alkaline phosphatase risedronate (30 mg daily for 2 months) was chosen as first‐line treatment. Also pamidronate (3 intravenous infusions of 60 mg, total dose 180 mg) could be used. Treatment was administered with the aim of restoring alkaline phosphatase;

  • If there was an inadequate response, participants could be re‐treated.

Co‐interventions: Analgesics and nonsteroidal anti‐inflammatory drugs for symptomatic and intensive treatment group

Outcomes

Outcomes reported in abstract

Primary endpoint: Radiologically‐confirmed clinical fracture.

Secondary endpoints:

• change in bone pain (assessed as participant reporting pain/no pain. Physicians asked to assess if they considered if reported bone pain was due to Paget's disease of bone);

• adverse events related to use of bisphosphonates;

• need for orthopaedic surgery;

• change in quality of life measures (assessed by Stanford Health Assessment Questionnaire Disability Index, EQ‐5D, SF‐36, arthritis‐specific version of SF‐36 (ASHI));

• change in hearing thresholds;

• withdrawals due to adverse events; 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 hospital, which was set to a level of 1.0).

Time points for measurement: Visits scheduled at 4 monthly intervals.

How were the outcomes measured: prospectively

Setting and date

39 secondary referral centres in the UK.

Period when the study was conducted: December 2001 to June 2004

Follow up period

Median 3 years (range 2 to 5 years)

Publication details and funding source

Language of publication: English.
Publication status: peer‐reviewed journal; full article.

Funding source: Supported by grants from the Arthritis Research Campaign UK (Ref. 13627), National Association for Relief of Paget’s Disease, Procter & Gamble Pharmaceuticals and Sanofi‐Aventis.

Declarations of interest among primary researchers:

• Stuart H Ralston: consultant for Procter & Gamble, Novartis and Merck.

• William D Fraser: consultant for Procter & Gamble, MSD, Novartis, Sanofi Aventis, Nycomed and Roche.

• Peter L Selby: consultant for Procter & Gamble, Novartis, Nycomed and Roche.

• Anne L Langston: received a travel bursary from Procter & Gamble and Sanofi‐Aventis.

• All other authors stated 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)

Low risk

Quote: "Patients were assigned to the treatment groups by an integrated telephone and web‐based randomization system"

Allocation concealment (selection bias)

Low risk

Quote: "Treatment allocation employed minimization to ensure that the treatment group were balanced with respect to key prognostic variables"

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "The study was not blinded".

Comment:

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Information provided by authors: The assessments of events were performed by individuals who were unaware of the treatment allocation

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Information provided by 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.

Comment: The risk of attrition bias was low for data at 2 years (minimum duration of follow‐up). The rate of losses to follow‐up at this point was 12% and 13% respectively. The risk of attrition bias is high for 36 or 48 months

Selective reporting (reporting bias)

Low risk

Study protocol available. All proposed outcomes were reported

Other bias

Low risk

Comment: The study design allowed the attending clinicians to choose different drugs within a specified treatment strategy. Evidence that the attending clinicians adhered to the allocated strategy came from the observation that alkaline phosphatase levels differed significantly between groups

Methods

RCT. Randomisation ratio: 1:1:1 (placebo: tiludronate 200 mg: tiludronate 400 mg).

Superiority design

Participants

Diagnostic criteria: Diagnosis confirmed by radiographic and clinical criteria.

Inclusion criteria: participants aged > 32 years and with serum alkaline phosphatase values at least twice ULN.

Exclusion criteria:

• no other metabolic skeletal disorders or medical problems that would interfere with assessments in this study;

• had not received pamidronate within 2 years or any other bisphosphonates or mithramycin within 6 months, or calcitonin or gallium nitrate within the previous 2 months;

• had not experienced fracture of a long bone, had not undergone skeletal surgery or received systemic glucocorticoid therapy in the past 6 months.

Number screened: not stated.

Number randomised: 139.

Number analysed: 134 (70 years, 54% male; percentages monostotic, symptomatic or previously treated for Paget's disease of bone not stated)

Interventions

Three parallel treatment groups; placebo and tiludronate in two different doses (200 mg, 400 mg) nightly for 12 weeks.

Co‐interventions: Calcium‐containing food and supplements were avoided around the time the study medication was taken

Outcomes

Outcomes reported in abstract

Primary endpoint: Mean percentage change from baseline in serum total alkaline phosphatase activity.

Secondary endpoints:

• change in bone pain (measured on Huskisson pain severity score (derived from a 10 cm VAS ranging from no pain (0 cm) to maximum pain (10 cm))

• adverse events related to use of bisphosphonates

• withdrawals due to adverse events.

Time points for measurement: Baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks.

How were the outcomes measured: prospectively

Setting and date

20 centres in the USA and Canada.

Period when the study was conducted: Not stated

Follow up period

6 months

Publication details and funding source

Language of publication: English.
Publication status: peer‐reviewed journal; full article.

Funding source: Research supported by Sanofi Winthrop Ltd.

Declarations of interest among primary researchers: Not stated

Notes

Data on the tiludronate groups were pooled for meta‐analysis

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "In a randomized, double‐blind, placebo‐controlled study... were enrolled at 20 centers throughout the USA and Canada"

Comment: Likely that the risk of bias was low because for a multicentre design, the allocation process should be centralized

Allocation concealment (selection bias)

Unclear risk

Insufficient information provided to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

"Double‐blind"

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement.

The risk is probably low for laboratory data because two laboratories were involved:

1. Routine biochemical and haematologic laboratory studies, urinary hydroxyproline was measured at SciCor (Indianapolis, IN, USA).

2. Urinary pyridinoline assays were performed at Ostex International (Seattle, WA, USA)

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Reasons for attrition and exclusion were reported. 2/91 (2%) participants were lost from the interventions group and 3/48 (65) participants from the placebo group

Selective reporting (reporting bias)

Unclear risk

Methods and results sections were consistent. Insufficient information to permit judgement. We did not have access to a trial register record or study protocol to know if there was a prespecified record of the studies outcomes.

Comment: Data for pain assessment were poorly reported

Other bias

Unclear risk

No other risks of bias found, but reporting was insufficient to permit judgement.

Methods

RCT. Randomisation ratio: 2:1 (pamidronate: zoledronate).

Superiority design

Participants

Diagnostic criteria: confirmed by bone scintigraphy and x‐ray of areas of increased isotope uptake.

Inclusion criteria: Presence of serum total alkaline phosphatase above ULN (298 IU/L) on 2 consecutive measurements and no treatment with bisphosphonates or other drugs affecting bone metabolism for at least 6 months before the study.

Exclusion criteria:

• major comorbidity;

• metabolic bone disease other than uncomplicated osteoporosis;

• recent fracture of Pagetic bone;

• clinically significant liver disease; and

• kidney impairment.

Number screened: not stated.

Number randomised: 90.

Number analysed: 89 (70 years, 64% male; percentage monostotic not stated, 99% symptomatic, 66.7% previously treated for Paget's disease of bone)

Interventions

2 parallel treatment groups; 4 mg single infusion of zoledronate or 30 mg infusion of pamidronate for 2 consecutive days every 3 months.

Co‐interventions: 1 g calcium and 800 IU cholecalciferol per day

Outcomes

Outcomes reported in abstract

Primary endpoint: Rate of therapeutic response (defined as normalisation of alkaline phosphatase levels or a reduction of at least 75% in total alkaline phosphatase excess).

Secondary endpoints:

• change in bone pain (pain was recorded as never pain, disappearance, decrease and no change. It was the participant's and investigator's decision whether or not pain was related to Paget's disease of bone);

• adverse events related to use of bisphosphonates;

• change in quality of life measures (measured by a validated Italian version of Stanford Health Assessment Questionnaire functional disability index);

• withdrawals due to adverse events; and

• mean percentage change from baseline in serum total alkaline phosphatase activity.

Time points for measurement: Baseline and 6 months.

How were the outcomes measured: prospectively

Setting and date

One centre in Siena, Italy.

Period when the study was conducted: Not stated

Follow up period

6 months

Publication details and funding source

Language of publication: English.
Publication status: peer‐reviewed journal; full article.

Funding source: Not stated.

Declarations of interest among primary researchers: No authors had conflicts of interest

Notes

The study was subdivided:

1. During the first 6 months participants were randomised to pamidronate or zoledronate (This was included study in the review).

2. After 6 months, participants who did not respond to pamidronate were crossed‐over to zoledronate or started on neridronate. (This was not included in the review because participants were not randomised)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "randomized study... randomization was stratified according to baseline alkaline phosphatase levels and previous bisphosphonate treatment (as a binary variable: yes or no)".

Comment: Random sequencing was probably computer‐generated; the randomisation was stratified

Allocation concealment (selection bias)

Unclear risk

Insufficient information provided to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Open‐label

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "29 of 30 patients receiving zoledronate and 60 of 60 patients receiving pamidronate completed the follow‐up at 6 mo".

Comment: Only one participant was lost to follow‐up at 6 months

Selective reporting (reporting bias)

Unclear risk

Methods and results sections were consistent. Insufficient information to permit judgement. We did not have access to a trial register record or study protocol to know if there was a prespecified record of the studies outcomes

Other bias

Unclear risk

No other risks of bias found, but reporting insufficient to permit judgement

Methods

RCT. Randomisation ratio: 1:1 (risedronate: etidronate).

Superiority design

Participants

Diagnostic criteria: confirmed by bone scintigraphy or x‐ray.

Inclusion criteria: participants aged 18 to 85 years, with serum alkaline phosphatase concentration of at least twice the ULN. Women had to be at least 1 year postmenopause or using contraception.

Exclusion criteria:

• evidence of organic or psychiatric disease that would prevent the participant completing the study;

• history of cancer (except skin cancer or cervical carcinoma in situ);

• history of hyperparathyroidism, hyperthyroidism or osteomalacia within 1 year before enrolment;

• markedly abnormal laboratory parameters;

• those who had received:

  • oral or parenteral glucocorticoid or anabolic steroids within 3 months of study commencement;

  • calcitonin;

  • vitamin D > 1000 IU/day or calcitriol 1.5 µg/week within 1 month before study commencement; or

  • any bisphosphonates, fluoride, plicamycin, gallium nitrate or parathyroid hormone within 6 months of study commencement.

Number screened: 179.

Number randomised: 123.

Number analysed: 103 (66 years, 69% males, 24% monostotic, 91% symptomatic, 72% previously treated for Paget's disease of bone)

Interventions

Two parallel treatment groups; oral risedronate 30 mg daily for 2 months and oral etidronate 400 mg for 6 months.

Co‐interventions: Not reported

Outcomes

Outcomes reported in abstract

Primary endpoint: Mean percentage change from baseline in serum total alkaline phosphatase activity.

Secondary endpoints:

• change in bone pain (measured on SF‐36);

• adverse events related to use of bisphosphonates;

• change in quality of life measures (measured on SF‐36);

• withdrawal due to adverse events; and

• relapse due to recurrence of increased serum alkaline phosphatase level (relapse was defined as ≥ 50% increase in serum alkaline phosphatase concentration from the lowest concentration and reaching at least twice the ULN.

Time points for measurement: Baseline and 1 through 6, 8, 10, 12, and 18 months for laboratory measures. Baseline, 2, 6 and 12 months for quality of life (including pain).

How were the outcomes measured: prospectively

Setting and date

12 study centres in the USA and Canada.

Period when the study was conducted: Not stated

Follow up period

12 months plus an optional 6 month extended follow‐up

Publication details and funding source

Language of publication: English
Publication status: peer‐reviewed journal; full article.

Funding source: Supported by Procter & Gamble Pharmaceuticals, Cincinnati, OH, USA.

Declarations of interest among primary researchers: Not stated

Notes

None

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Patients were assigned unique, sequential identification numbers according to the chronological order of entry at each of the 12 centers and were stratified into those who had, and those who had not, received previous etidronate treatment. Within each center, and within each stratum of previous etidronate use, patients were assigned to one of the two treatment groups according to a randomisation schedule generated using SAS Version 6.07 PLAN procedure (SAS Institute, Cary, NC)".

Allocation concealment (selection bias)

Low risk

Computerised random number generator was used

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Double blind design".

Comment: Probably done.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information provided to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: Although the authors stated that the study included an intention‐to‐treat analysis:

• the study reported a total follow‐up period of 12 months for all participants and an optional 6 month extended follow‐up (total study period 18 months). However, neither the number of participants who were followed‐up for at least 12 months nor reasons for missing outcome data are clearly explained in the text.

• according to Table 2 (Results) only 3 participants were excluded from the final data (60 vs. 60 participants). However, in the text the authors stated different numbers of participants: "Of the patients for whom data were also available at month 12, 62% (33 of 53) in the risedronate group and 10% (5 of 50) in the etidronate group were still in biochemical remission." (50 vs. 53 participants)

Selective reporting (reporting bias)

Unclear risk

Methods and results sections were consistent. Insufficient information to permit judgement. We did not have access to a trial register record or study protocol to know if there was a prespecified record of the studies outcomes

Other bias

Unclear risk

There were no data on exposure to co‐interventions other than bisphosphonates. No other risks of bias found, but reporting insufficient to make judgement

Methods

RCT. Randomisation ratio: 2:1 (alendronate: placebo).

Superiority design

Participants

Diagnostic criteria: diagnosis established by finding hyperphosphatasia and characteristic radiographic and scintigraphic features.

Inclusion criteria: participants diagnosed as active Paget's disease of bone.

Exclusion criteria:

• treatment for Paget's disease of bone with drugs other than analgesic in 3 months prior to trial enrolment;

• taking medication or suffering from disorders likely to affect skeletal metabolism.

Number screened: not stated.

Number randomised: 15.

Number analysed: 15 (67 years, 60% male, % monostotic not stated, 87% symptomatic, 66% previously treated for Paget's disease of bone)

Interventions

Two parallel treatment groups: intravenous alendronate 10 mg/day for 5 days and placebo.

Co‐interventions: Not reported

Outcomes

Outcomes reported in abstract:

Primary endpoint: Mean percentage change from baseline in serum total alkaline phosphatase activity.

Secondary endpoints:

• change in bone pain (measurement tool used not reported);

• adverse events related to use of bisphosphonates;

• withdrawal due to adverse events.

Time points for measurement: Baseline and 2, 3 and 4 weeks from the start of treatment and monthly thereafter for 6 months.

How were the outcomes measured: prospectively

Setting and date

One centre in Sheffield, UK.

Period when the study was conducted: Not stated

Follow up period

6 months.

Comment: The blind was broken 4 weeks after the start of treatment. The 10 participants who received treatment with alendronate were additionally followed for 6 months. The 5 participants who received placebo were allowed to withdraw from the study after the blind was broken

Publication details and funding source

Language of publication: English
Publication status: peer‐reviewed journal; full article.

Funding source: Supported by a Programme Grant from the Medical Research Council and by Merck, Sharp and Dohme Research Laboratories, Woodbridge, NJ, USA and Harlow, UK.

Declarations of interest among primary researchers: Not stated

Notes

None

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "A group of 15 patients with active Paget’s disease of bone were randomised prospectively".

Comment: Insufficient information provided to permit judgement

Allocation concealment (selection bias)

Unclear risk

Insufficient information provided to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "receive 5 days of treatment with either alendronate (10 mg/day) or placebo under double‐blind conditions".

Comment: Probably done.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information provided to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

High risk

Quote: "The blind was broken 4 weeks after the start of treatment. The 10 participants who received treatment with alendronate were additionally followed for 6 months. The 5 participants who received placebo were allowed to withdraw from the study after the blind was broken."

Comment: The follow‐up was different for participants in the placebo and experimental groups (e.g. data on urinary hydroxyproline and serum alkaline phosphatase (Figure 1) were registered to different weeks from the start of treatment for alendronate or placebo)

Selective reporting (reporting bias)

High risk

We did not have access to a trial register record or study protocol to know if there was a prespecified record of the studies outcomes.

Comment: Pain data were reported, but pain was not defined as an outcome. There was no reporting of how pain was assessed. There were no data reported on adverse effects.

Other bias

Unclear risk

There were no data on exposure to co‐interventions other than bisphosphonates. No other risks of bias found, but reporting was insufficient to permit judgement

Methods

RCT. Randomisation ratio: 1:1 (etidronate: etidronate plus calcitonin).

Superiority design

Participants

Diagnostic criteria: Iliac crest bony biopsy, skeletal radiography and scintigraphy were performed to confirm the diagnosis of Paget’s disease.

Inclusion criteria: participants with biochemically active Paget’s disease whose bone pain was unresponsive to simple analgesia or nonsteroidal anti‐inflammatory agents.

Exclusion criteria: Not stated.

Number screened: not stated.

Number randomised: 44.

Number analysed: 44 (age and sex not stated; percentage monostotic not stated, 100% symptomatic, 10% previously treated for Paget's disease of bone)

Interventions

Two parallel treatment groups: oral etidronate 400 mg and oral etidronate 400 mg in combination with subcutaneous calcitonin 100 MRC units thrice weekly for six months.

Co‐interventions: Participants were on a constant calcium low gelatin diet.

Outcomes

Outcomes reported in abstract

Primary endpoint: Mean percentage change from baseline in serum total alkaline phosphatase activity.

Secondary endpoints:

• change in bone pain (assessment tool not reported);

• radiologically‐confirmed clinical fractures; and

• adverse events related to use of bisphosphonates.

Time points for measurement: Baseline, monthly during treatment, and every 2 to 3 months for an additional 6 months period.

How were the outcomes measured: prospectively

Setting and date

One centre in Nottingham, UK.

Period when the study was conducted: Not stated

Follow up period

12 months

Publication details and funding source

Language of publication: English
Publication status: peer‐reviewed journal; full article.

Funding source: Not stated.

Declarations of interest among primary researchers: Not stated

Notes

The study randomised a group of participants to be treated with etidronate or etidronate plus calcitonin. The authors also compared these two groups with data accumulated from participants who received calcitonin alone prior to the introduction of etidronate in the metabolic unit (28 participants); this group was excluded because participants were not randomised

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "Forty‐four sequential patients were randomised to treatment".

Comment: Insufficient information provided to permit judgement

Allocation concealment (selection bias)

Unclear risk

Insufficient information provided to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "patients were randomised to treatment with either EHDP 400 mg daily alone (21 patients) or in combination with SCT 100 MRC units thrice weekly (23 patients)".

Comment: Because there was no mention of placebo, it is likely that one group was treated with oral drugs alone and the other with a combination of oral and subcutaneous drugs; hence, blinding was not possible

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information provided to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "Two patients treated with EHDP defaulted from follow‐up but the other 70 were reevaluated in the metabolic unit after 6 months".

Comment: Attrition rate was low; only two participants were lost to follow‐up. The proportion of missing outcomes compared with observed event risk was insufficient to have a clinically‐relevant impact on the intervention effect estimate

Selective reporting (reporting bias)

High risk

We did not have access to a trial register record or study protocol to know if there was a prespecified record of the studies outcomes.

Comment: There are some contradictions between methods and results sections.

1. To be included, participants had pain due to Paget's disease of bone ("Patients with biochemically active Paget’s disease whose bone pain was unresponsive to simple analgesia or nonsteroidal anti‐inflammatory agents were studied"). However, the method to assess pain was not described, although pain should be measured during the study ("If the bone pain remained severe and the disease was biochemically active treatment was continued for a further 6 months", "Treatment was continued for a further 6 months in 38 participants (11 SCT + EHDP: 21 SCT: 6 EHDP) who were still symptomatic with a persistently elevated disease activity".

2. Although fractures were not defined as an outcome, these were reported ("four patients with fissure fractures... nontraumatic extension of fissure fractures occurred in two patients, one given combined treatment and the other given EHDP").

3. Authors stated that "patients were seen monthly to monitor clinical and biochemical responses, side‐effects and compliance". However, adverse events were not reported in the study results

Other bias

Unclear risk

No other risks of bias found, but reporting insufficient to make judgement

Methods

RCT. Randomisation ratio: 1:1:1 (etidronate plus 1α‐hydroxyvitamin D: etidronate plus placebo: placebo plus placebo).

Superiority design

Participants

Diagnostic criteria: Radiological and bone scan evidence of Paget's disease of bone.

Inclusion criteria: Symptomatic participants.

Exclusion criteria: Treatment for Paget's disease of bone in the 12 months before study commencement.

Number screened: not stated.

Number randomised: 32.

Number analysed: 29 (age and sex not reported; 31% monostotic, 100% symptomatic, 37.5% previously treated for Paget's disease of bone)

Interventions

Three parallel treatment groups: oral etidronate 400 mg plus 1α‐hydroxyvitamin D 0.5 μg, oral etidronate 400 mg plus placebo and placebo plus placebo for three months.

Co‐interventions: participants received other medications according to routine practice (e.g. analgesics, nonsteroidal anti‐inflammatory drugs) (information provided by authors).

Outcomes

Outcomes reported in abstract

Primary endpoint: Mean percentage change from baseline in serum total alkaline phosphatase activity

Secondary endpoints: change in bone pain (linear analogue technique with a scale ranging from 0 (no pain) to 30 (very severe pain)).

Time points for measurement: Baseline, and after 2, 8 and 12 weeks on drug therapy.

How were the outcomes measured: prospectively

Setting and date

One centre in Glasgow, UK.

Period when the study was conducted: not stated

Follow up period

3 months

Publication details and funding source

Language of publication: English
Publication status: peer‐reviewed journal; full article.

Funding source: Partially supported by a grant to BFB from the Scottish Hospital Endowments Research Trust and a grant to ITB from Brocades (UK) Ltd. The 1α‐hydroxyvitamin D and placebo tablets were supplied by Leo Laboratories Ltd.

Declarations of interest among primary researchers: not stated

Notes

Data on etidronate plus 1α‐hydroxyvitamin D and etidronate plus placebo groups were pooled for meta‐analysis.

Transiliac bone biopsies were obtained before therapy in all cases and after therapy in 28 participants. Bone histomorphometry data were reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "On entry to the trial patients were randomised".

Information provided by authors: Allocation by referring to random numbers

Allocation concealment (selection bias)

Low risk

Information provided by authors: Investigators were blinded to treatment allocation

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "double blind"

Information provided by authors: A double dummy was used with placebo/placebo, etidronate/placebo and etidronate/1α‐hydroxyvitamin D

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Information provided by authors: Investigators were blinded to treatment when assessing outcome

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "There were three withdrawals from the trial after randomisation".

Comment: The rate of withdrawals (and reasons) were reported

Selective reporting (reporting bias)

High risk

We did not have access to a trial register record or study protocol to know if there was a prespecified record of the studies outcomes.

The authors reported symptoms and side effects and described only one adverse event ("one patient who developed increasing pain and radiological deterioration at the site of an asymptomatic pseudofracture of the tibia"). However, at the start of the results section the authors described another adverse event which was not included in the "symptoms and side effects" paragraph ("1 patient in Group A stopped medication because of dyspepsia"). Data on hypercalcaemia are on biochemistry ("One patient... developed mild hypercalcaemia"). There were no other data on adverse events.

Information provided by authors: Adverse events were not systematically recorded

Other bias

Unclear risk

No other risks of bias found, but reporting insufficient to make judgement

Methods

RCT. Randomisation ratio: 1:1:1:1:1 (placebo: tiludronate 100 mg: tiludronate 200 mg: tiludronate 400 mg: tiludronate 800 mg).

Superiority design

Participants

Diagnostic criteria: Paget's disease of bone with characteristic radiologic lesions and/or with 99mTc bisphosphonates scintigraphic evidence of local increase in bone turnover.

Inclusion criteria: Serum alkaline phosphatase levels were at least twice the ULN.

Exclusion criteria:

• free of kidney, liver, neurologic, haematologic, inflammatory and immune disorders.

• taking no medications known to interfere with bone metabolism. Different minimal washout periods prior to the study were established for bone drugs: 6 months for etidronate, 2 months for calcitonin, 2 years for tiludronate and 2 years for clodronate.

Number screened: not stated.

Number randomised: 149.

Number analysed: 149 (69 years, 54 % male, % monostotic not stated, % symptomatic participants not stated, 82% previously treated for Paget's disease of bone)

Interventions

The study was divided into 2 periods. In the first period there were five parallel treatment groups: placebo (4 x placebo capsules), tiludronate 100 mg (2 x placebo and 2 x 50 mg tiludronate capsules), tiludronate 200 mg (4 x capsules 50 mg tiludronate), tiludronate 400 mg (4 x capsules 100 mg), tiludronate 800 mg (4 x capsules 200 mg tiludronate). All participants took 2 capsules at 10.00 am and 2 capsules at 4.00 pm daily for 3 months.

In the second period all participants received 4 placebo capsules.

The investigators initiated tiludronate therapy during the second period for participants experiencing a lack of efficacy (participants were considered discontinued from the study).

Co‐interventions: Not reported

Outcomes

Outcomes reported in abstract

Primary endpoint: Mean percentage change from baseline in serum total alkaline phosphatase activity.

Secondary endpoints:

• change in bone pain (Huskisson VAS; range 0 cm (no pain) to 10 cm (maximal pain). A pain index was derived from pain severity and time course scores. Only pain in bones or joints in which Pagetic lesions had been clearly demonstrated by radiography or bone scans were considered. For each painful bone or joint, the participant rated pain severity (mild = 1, moderate = 2, severe = 3) and time course (on motion = 1, intermittent = 2, constant = 3). By multiplying the scores for severity and time course, a pain index was calculated for each site. The scores for all sites were added to yield an overall pain index;

• adverse events related to use of bisphosphonates;

• withdrawal due to adverse events; and

• achieved normalised alkaline phosphatase level.

Time points for measurement: Baseline and monthly intervals.

How were the outcomes measured: prospectively

Setting and date

29 centres in Belgium, France and USA.

Period when the study was conducted: Not stated

Follow up period

6 months

Publication details and funding source

Language of publication: English
Publication status: peer‐reviewed journal; full article.

Funding source: Supported by Sanofi Research, Montpellier, France.

Declarations of interest among primary researchers: Not stated

Notes

Data on tiludronate groups were pooled for meta‐analysis

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "double‐blind, randomised, placebo‐controlled study".

Comment: Insufficient information provided to permit judgement, but probably low risk because the allocation process should have been centralized because the study involved 29 centres in different countries

Allocation concealment (selection bias)

Unclear risk

Insufficient information provided to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "double‐blind, randomised, placebo‐controlled study".

Comment: Probably done.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quote: "All biochemical determinations were performed at
a central location throughout the period of study."

Comment: Insufficient information provided, but likely low risk because it is unlikely that the blinding was broken in a central location

Incomplete outcome data (attrition bias)
All outcomes

High risk

Quote: "Follow up assessments were available for all 149 patients."

Quote: "Thirty‐five patients withdrew prematurely from the study. The reasons were lack of efficacy in 9, adverse events in 15, at the patient’s request in 4, lost to follow‐up in 4, and miscellaneous reasons unrelated to treatment in 3. There was no relationship noted between the dosage of tiludronate and the number of study withdrawals."

Comment: Although the reasons for missing outcome data were explained and withdrawals balanced between groups, the proportion of missing outcomes (25%) compared with observed event risk is enough to induce clinically‐relevant bias in intervention effect estimate

Selective reporting (reporting bias)

Unclear risk

Methods and results sections were consistent. Insufficient information to permit judgement. We did not have access to a trial register record or study protocol to know if there was a prespecified record of the studies outcomes

Other bias

Unclear risk

There were no data on exposure to co‐interventions other than bisphosphonates. No other risks of bias found, but reporting insufficient to permit judgement

Methods

RCT. Randomisation ratio: 1:1 (placebo: alendronate 40 mg).

Superiority design

Participants

Diagnostic criteria: Paget’s disease of bone documented by standard clinical, radiological or scintigraphic methods or both.

Inclusion criteria:

1. participants who had not received bisphosphonate therapy previously were required to have a baseline serum alkaline phosphatase activity at least twice the ULN.

2. participants who had taken bisphosphonate therapy previously were required to have a baseline serum alkaline phosphatase activity at least four times the ULN and exceeding the previous post‐treatment nadir by an amount ≥ the ULN range.

Exclusion criteria:

1. Active upper gastrointestinal disease in the previous year or a history of surgery for peptic ulcer disease.

2. Medical conditions or taking medications likely to affect bone metabolism.

Number screened: not stated.

Number randomised: 55.

Number analysed: 53 (70 years, 56 % male, percentage monostotic or symptomatic not stated, 35% previously treated for Paget's disease of bone)

Interventions

Two parallel treatment groups: placebo and oral alendronate 40 mg daily for 6 months.

Co‐interventions: Calcium (450 mg to 500 mg) and vitamin D (400 IU to 600 IU)

Outcomes

Outcomes reported in abstract:

Primary endpoint: Mean percentage change from baseline in serum total alkaline phosphatase activity.

Secondary endpoints:

• change in bone pain (assessed using the Brief Pain Inventory);

• adverse events related to use of bisphosphonates;

• withdrawal due to adverse events; and

• achieved normalised alkaline phosphatase level.

Time points for measurement: baseline, 3 and 6 months.

How were the outcomes measured: prospectively

Setting and date

Three sites in Australia, New Zealand, and UK.

Period when the study was conducted: Not stated

Follow up period

6 months

Publication details and funding source

Language of publication: English.
Publication status: peer‐reviewed journal; full article.

Funding source: Supported by Merck Research Laboratories, Rahway, NJ, USA.

Declarations of interest among primary researchers: Not stated

Notes

Bone biopsy conducted for 28 participants. Bone histomorphometry data reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Patients were randomly assigned".

Comment: Probably done because the study was multicentre, involving 3 countries

Allocation concealment (selection bias)

Unclear risk

Insufficient information provided to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "The study was double‐blinded".

Comment: Insufficient information provided to permit judgement, but probably done

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Radiographs were all evaluated by one skeletal radiologist, who was blinded with respect to film sequence and treatment allocation". "Bone biopsy: Each specimen was coded, so that the reader was unaware of the subjects' drug therapy..." Adverse events that were considered by the blinded investigator to be possibly treatment related occurred in..."

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "No subjects withdrew from the study because of drug side effects.

Comment: Attrition rate was low because only two participants did not complete the study in the placebo group but none in the alendronate group.

The authors did not explain the reasons for not completing the trial for these two participants. However, both participants were from the placebo group and the proportion of missing outcomes compared with observed event risk were insufficient to have a clinically relevant impact on the intervention effect estimate

Selective reporting (reporting bias)

Unclear risk

Methods and results sections were consistent. Insufficient information to permit judgement. We did not have access to a trial register record or study protocol to know if there was a prespecified record of the studies outcomes.

Other bias

Unclear risk

No other risks of bias found, but reporting was insufficient to permit judgement

Methods

RCT: Randomisation ratio: 1:1:1 (placebo: ibandronate 6 mg: ibandronate 12 mg).

Superiority design

Participants

Diagnostic criteria: Paget’s disease of bone confirmed radiologically.

Inclusion criteria: Serum alkaline phosphatase activities at baseline at least twice the upper limit of the reference range.

Exclusion criteria: Other medical conditions, or on medications that affect bone or calcium metabolism.

Number screened: not stated.

Number randomised: 25.

Number analysed: 23 (73 years, 74 % male, percentages monostotic and symptomatic not stated, 64% previously treated for Paget's disease of bone)

Interventions

Three parallel treatment groups: placebo (infusions of normal saline at baseline and at 1 month), ibandronate 6 mg (infusions of 6 mg of ibandronate at baseline and normal saline at 1 month), ibandronate 12 mg (infusions of 6 mg of ibandronate at both baseline and 1 month).

Co‐interventions: None (information provided by authors)

Outcomes

Outcomes reported in abstract:

Primary endpoint: Mean percentage change from baseline in serum total alkaline phosphatase activity.

Secondary endpoints: Number who achieved normalised alkaline phosphatase level.

Time points for measurement: Not reported. At least at baseline, 3, 6 and 12 months.

How were the outcomes measured: prospectively

Setting and date

One centre in Auckland, New Zealand.

Period when the study was conducted: Not stated

Follow up period

6 months (12 months, see notes)

Publication details and funding source

Language of publication: English.
Publication status: peer‐reviewed journal; full article.

Funding source: Supported by the Health Research Council of New Zealand and Roche Products (NZ) Ltd.

Declarations of interest among primary researchers: not stated

Notes

Ibandronate group data were pooled for meta‐analysis.

Participants were followed for an additional 6 month period after finishing the first 6 months of the study. In this second part of the study, 6 placebo group participants (67%) were given ibandronate in a non‐randomised way. Data from this second part of the study were not included in this review.

In 2017 the authors published a manuscript with data from original participants after 10 years follow up

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Patients were randomly allocated to one of three groups using a minimization algorithm to ensure balance between groups for alkaline phosphatase level".

Quote: "Six subjects who had placebo at both of these time points subsequently were given ibandronate 6 mg at 6 months, so posttreatment data are shown for 20 subjects"

Quote: "Because the focus of this study was on relative response of markers to ibandronate, the pre‐ and posttreatment data in the two ibandronate groups and in those patients from the ‘placebo’ group who went on to have ibandronate have been pooled, so that every subject in the study provides a pre‐ and 6 months post‐ibandronate value".

Comment: Although initially participants were randomised, the authors pooled data from participants who were initially randomised to ibandronate with data from placebo participants who received ibandronate in a 6 month study extension.

Note: Although the study general assessment of risk of bias for random sequence generation is high, we assessed risk as unclear because on we included data from the first part of the study only in the meta‐analysis

Allocation concealment (selection bias)

Unclear risk

Comment: As for assessment of random sequence generation, although for the first 6 months the authors probably concealed allocation, when finishing the first part of the study, they treated two thirds of placebo participants with ibandronate so they knew participant allocation at that time.

Note: Although the study general assessment of risk of bias for allocation concealment is high, we assess the risk as unclear because, on meta‐analysis, we introduce only data from the first part of the study.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Information provided by authors: Infusions were prepared by staff members who had no contact with the participants, so that study staff and participants were blinded to treatment received

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Information provided by authors: Outcome assessment was blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "'Placebo' group (nine patients), received infusions of normal saline at baseline and at 1 month, the ‘6 mg’ group (nine patients, eight with follow‐up data) received ibandronate 6 mg at baseline and placebo at 1 month, and the ‘12 mg’ group (seven patients, six with follow‐up data) received ibandronate 6 mg at both baseline and 1 month".

Comment: Follow‐up data were provided and missing outcome data are likely balanced; however, reasons for missing outcomes were not explained.

The proportion of missing outcomes compared with observed event risk is not enough to have a clinically‐relevant impact on the intervention effect estimate

Selective reporting (reporting bias)

High risk

Information provided by authors: Adverse events were not systematically recorded

Other bias

Unclear risk

No other risks of bias found, but reporting was insufficient to permit judgement

Methods

RCT. Randomisation ratio: 1:1 (zoledronate acid: risedronate).

Non inferiority design

Participants

Diagnostic criteria: Paget’s disease of bone was confirmed by x‐ray, magnetic resonance imaging, computerized tomography, radio‐isotope imaging, etc.

Inclusion criteria:

• aged over 30 years;

• serum alkaline phosphatase activities at baseline more than twice the upper limit of the reference range.

Exclusion criteria:

• Serum 25‐hydroxyvitamin D level < 15 ng/mL (37 nmol/L);

• Primary hyperparathyroidism;

• evidence of liver or kidney disease;

• history of uveitis or iritis

• upper gastrointestinal disorders that might interfere with adherence to the protocol;

• diabetic nephropathy or retinopathy;

• use of therapy specifically for Paget’s disease in the preceding 180 days;

• allergic reaction to bisphosphonates;

• calculated creatinine clearance < 30 mL/min at baseline; or

• evidence of vitamin D deficiency.

Number screened: 688 (371 + 317).

Number randomised: 357 (185 + 172).

Number analysed: 349 (70 years, 67.7% male; percentages monostotic or symptomatic not stated; 54% previously treated for Paget's disease of bone).

An extension study of the core trial was published including participants who had therapeutic response defined as normalisation of the alkaline phosphatase level or a reduction of at least 75% in alkaline phosphatase excess (the difference from the midpoint of the reference range) at 6 months of treatment.

Number screened for the extension study: 296 (169 responders from 182 participants from the zoledronate group + 127 responders from 175 participants from the risedronate group).

Number analysed for the extension study: 267 (152 responders from the zoledronate group + 115 responders from the risedronate group) (70 years; sex, monostotic status and symptomatic participants not stated; 100% previously treated for Paget's disease of bone)

Interventions

Two parallel treatment groups: zoledronate (single 5 mg infusion zoledronate at baseline followed by placebo tablets daily for 60 days), risedronate (saline infusion followed by 30 mg tables of risedronate daily for 60 days).

Co‐interventions: All participants received 1 g calcium per day and 400 IU to 1000 IU calciferol per day.

No further interventions were added after treatment in the core trial for the extension study

Outcomes

Outcomes reported in abstract:

Primary endpoint: Proportion of participants who had therapeutic response. Therapeutic response was defined as normalisation of the alkaline phosphatase level or a reduction of at least 75% in the alkaline phosphatase excess (the difference from the midpoint of the reference range) at 6 months.

Secondary endpoints:

• change in bone pain (assessed using SF‐36 domain bodily pain (range from 0 (worst) to 100 (best)) and Brief Pain Inventory‐Short Form (BPI‐SF). This scale values are 0 to 10, a lower score means little to no pain while a higher score means greater pain. Bone pain was not specifically assessed);

• radiologically‐confirmed clinical fractures (data not reported);

• adverse events related to use of bisphosphonates;

• change in quality of life measures (assessed on SF‐36);

• withdrawals due to adverse events; and

• relapse due to recurrence of increased serum alkaline phosphatase level.

Time points for measurement: Not reported. Probably at baseline, 10 days, 1, 2, 3 and 6 months according to x‐axis graph data.

Quote: "Physical examinations, hematologic tests, and serum chemical tests were performed regularly throughout the six‐month study. Serum creatinine and urinary protein were measured 9 to 11 days after intravenous dosing".

How were the outcomes measured: prospectively.

Relapse rate was the primary endpoint for the extension study. Relapse was defined as a return of alkaline phosphatase to within 20% of the pre‐treatment baseline value. Partial relapse was defined as an alkaline phosphatase level that was both 50% above its 6 month value and 1.25 times the ULN range. Outcomes were monitored at 6 monthly visits

Setting and date

76 centres in 10 countries (Australia, Belgium, Canada, France, Germany, New Zealand, South Africa, Spain, UK, USA).

Period when the study was conducted: January 2002 to March 2004.

Period when the extension study was conducted: Follow up covers the period from the end of the core trials to 29 January 2009

Follow up period

6 months.

6.5 years observation period in the extension study: median follow‐up time from the beginning of the core study was 5.0 years for zoledronate and 3.3 years for risedronate (patient‐years of follow‐up were 574 years and 340 years respectively)

Publication details and funding source

Language of publication: English.
Publication status: peer‐reviewed journal; full article.

Funding source: Supported by a research grant from Novartis Pharma AG, Basel, Switzerland.

Declarations of interest among primary researchers:

• Drs. Luchi, Mesenbrink, Pak, Richardson, Saidi, and Su and Mr. Zelenakas are employees of Novartis and have stock options or other ownership interest in the company.

• Dr. Richardson is the originator of a patent application for the use of zoledronic acid in the treatment of postmenopausal osteoporosis by a once‐yearly intravenous infusion. He receives no royalties from this patent.

• Dr. Brown reports having received consulting and lecture fees from Novartis and Sanofi‐Aventis/Procter & Gamble and grant support from Novartis and Sanofi‐Aventis.

• Dr. Fraser reports having received consulting fees and lecture fees from Merck Sharpe & Dohme; consulting fees from Novartis, Nycomed, and Roche; lecture fees from Bayer, Boehringer Ingelheim, Boehringer Mannheim/Roche, Procter & Gamble/ Aventis, and Lilly; and grant support from Action Research, the Arthritis Research Campaign, the Biotechnology and Biological Sciences Research Council, Lilly, the Medical Research Council, Merck Sharpe & Dohme, Procter & Gamble, Remedi, Roche, and the Wellcome Trust.

• Dr. Hosking reports having received consulting fees from Merck Sharpe & Dohme, Novartis, Pfizer, and Roche; lecture fees from Lilly, Merck Sharpe & Dohme, and Novartis; and grant support from Lilly, Merck Sharpe & Dohme, Novartis, the ARC Clinical Trials Collaboration, the National Association for the Relief of Paget’s Disease, and the Alliance for Better Bone Health.

• Dr. Lyles reports having received consulting and lecture fees from Novartis and Procter & Gamble and grant support from Novartis, Procter & Gamble/Aventis, and the National Institute of Aging. Dr. Lyles is listed as a coinventor, with Novartis Pharmaceuticals, on a use patent for zoledronic acid (U.S. Provisional Patent Application No. 60/411,067, “Methods for preventing or reducing secondary fractures after hip fracture”).

• Dr. Miller reports having received consulting and lecture fees from Eli Lilly, Merck, Procter & Gamble, and Roche; consulting fees from Wyeth/Ayerst; lecture fees from Amgen and Novartis Pharmaceuticals; and grant support from Amgen, Eli Lilly, Merck, Novartis Pharmaceuticals, Procter & Gamble, and Roche.

• Dr. Reid reports having received consulting fees from Amgen, Merck, Novartis, and Procter & Gamble and grant support from Merck, Amgen, Novartis, the Health Research Council of New Zealand, and the Lactopharma Consortium.

Notes

The authors reported pooled data from two identical RCTs.

Participants identified as treatment responders were entered to an extended observation period including only those whose alkaline phosphatase was normal at completion of the core study.

Bone biopsies were performed for 22 participants (12 zoledronate acid and 10 risedronate). Bone histomorphometry data were reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Patients were randomly assigned in a double‐blind fashion through an interactive voice‐response system".

Comment: Probably done; authors describe a telephone system for sequence generation

Allocation concealment (selection bias)

Low risk

Study was conducted using a central allocation system (telephone)

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Patients were randomly assigned in a double‐blind fashion".

Comment: Probably done; placebo treatment is reported.

The risk of bias was judged as high risk for the extension studies because much of the extended follow‐up was conducted with participants and doctors knowing what treatment they received in the core trial (information provided by authors).

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Measurements were made by Covance Central Laboratory Services"

Information provided by authors: Outcome assessment was blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "All efficacy variables, except the time to a therapeutic response, were analysed according to the modified intention‐to‐treat principle, which required patients to have a baseline and at least one post‐baseline measurement of alkaline phosphatase."

Comment: Participant flow diagram including reasons for losses to follow‐up was included. MIssing outcome data were balanced between interventions and the proportion of missing outcomes compared with observed event risk was insufficient to have a clinically relevant impact on the intervention effect estimate.

The risk of bias was judged as high risk for the extension studies because only participants who responded to treatment were included in the follow‐up. Participants who relapsed or whose physicians provided further treatment for Paget's disease were discontinued from the study during the follow‐up.

Selective reporting (reporting bias)

High risk

Comment: Brief Pain Inventory‐Short Form (BPI‐SF) was stated as a secondary outcome measure in the study characteristics in the trial registry record, but was not reported in the study publication.

Data on fractures were not reported in the study publication but were proposed in the trial registry record

Other bias

Unclear risk

No other risks of bias found, but reporting was insufficient to permit judgement

Methods

RCT. Randomisation ratio: 1:1:1 (tiludronate 400 mg 3 months, tiludronate 400 mg 6 months; etidronate 400 mg 6 months).

Superiority design

Participants

Diagnostic criteria: Paget's disease of bone was confirmed by the presence of radiologically evident lesions characteristic of the disease.

Inclusion criteria: Serum alkaline phosphatase concentration at least twice the ULN range.

Exclusion criteria:

• treated during the previous 6 months with either etidronate or tiludronate, or during the previous 2 years with any other bisphosphonate;

• those treated previously (> 6 months earlier) with tiludronate were eligible if their serum alkaline phosphate concentration at entry exceeded twice that obtained at the end of the previous tiludronate treatment;

• treated during the previous 2 months with mithramycin or calcitonin;

• taking any medication or have any disorders likely to affect skeletal and calcium metabolism; and

• free of active liver, kidney, or haematologic disorders.

Number screened: Not stated.

Number randomised: 234.

Number analysed: 234 (69 years, 59% males, % monostotic not stated, 74% symptomatic participants, 71% previously treated for Paget's disease of bone)

Interventions

Three parallel treatment groups: tiludronate 400 mg 3 months (2 x 200 mg tiludronate tablets and 2 x etidronate placebo capsules during the first 3 months followed by 2 x tiludronate placebo tablets and 2 x etidronate placebo capsules during the second 3 months), tiludronate 400 mg 6 months (2 x 200 mg tiludronate tablets and 2 x etidronate placebo capsules for 6 months) and etidronate 400 mg 6 months (2 x 200 mg etidronate capsules and 2 tiludronate placebo tablets for 6 months).

Co‐interventions: Not reported

Outcomes

Outcomes reported in abstract:

Primary endpoint: Proportion of participants who had a response to treatment. Response to treatment was defined as a reduction of at least 50% in serum alkaline phosphatase concentration after a 3 month treatment period.

Secondary endpoints:

• change in bone pain (measured on the Huskisson VAS (10 cm scale ranging from no pain (0 cm) to maximal pain (10 cm));

• radiologically‐confirmed clinical fractures;

• adverse events related to use of bisphosphonates;

• withdrawal due to adverse events; and

• normalised alkaline phosphatase level.

Time points for measurement: Baseline, 3 months, 6 months.

How were the outcomes measured: prospectively

Setting and date

85 centres in 6 countries (Belgium, France, Germany, Italy, Netherlands, Spain).

Period when the study was conducted: February 1991 to September 1992

Follow up period

6 months

Publication details and funding source

Language of publication: English.
Publication status: peer‐reviewed journal; full article.

Funding source: Supported by Sanofi Recherche, Montpellier, France.

Declarations of interest among primary researchers: Not stated

Notes

Data on tiludronate groups were pooled for meta‐analysis

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "Patients were randomly allocated into 1 of 3 treatment groups."

Comment: Insufficient information provided.

Allocation concealment (selection bias)

Unclear risk

Insufficient information provided to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "The study was a double‐blind, randomized, multicenter, parallel‐group comparison." "According to the randomisation, patients received 4 doses daily: 2 200 mg tiludronate tablets and 2 etidronate placebo capsules during the first 3 months followed by 2 tiludronate placebo tablets and 2 etidronate placebo capsules during the second 3 months, 2 200 mg tiludronate tablets and 2 etidronate placebo capsules for 6 months, or 2 200‐mg etidronate capsules and 2 tiludronate placebo tablets for 6 months."

Comment: Probably done

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quote: "All samples were analysed at a central laboratory (Cerba Laboratories, Cergy‐Pontoise, France)."

Comment: Probably done for laboratory assessment. The information provided was insufficient to judge the blinding of outcome for clinical assessment

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "Of the 234 patients enrolled, 30 (12.8%) discontinued treatment before completing the 6 months of the study: 14 in the tiludronate 3‐month group, 11 in the tiludronate 6‐month group, and 5 in the etidronate group." "Intent‐to‐treat analyses were conducted." "For dichotomous variables, cases with missing data were considered as treatment failures."

Comment: Proportion of missing data were reported. Although the number of participants who discontinued treatment from both tiludronate groups was twice the number in the etidronate group, the proportion of missing outcomes compared with observed event risk was insufficient to have a relevant impact of the effect estimate

Selective reporting (reporting bias)

Unclear risk

Methods and results sections were consistent. Insufficient information to permit judgement. We did not have access to a trial register record or study protocol to know if there was a prespecified record of the studies outcomes

Other bias

Unclear risk

No other risks of bias found, but reporting was insufficient to permit judgement

Methods

RCT: Randomisation ratio: 1:1 (alendronate 40 mg: etidronate 400 mg).

Superiority design

Participants

Diagnostic criteria: Paget's disease of bone was confirmed by standard clinical, radiological or scintigraphic imaging or both methods

Inclusion criteria: Serum alkaline phosphatase at least twice the ULN if the participant had never been treated with bisphosphonates or plicamycin, or at least 4 times the ULN if the participant had received such therapy at any time in the past.

Exclusion criteria:

• treatment with any bisphosphonates or plicamycin within 12 months or calcitonin within 3 months preceding screening;

• osteolytic Pagetic lesion of a weight‐bearing bone that may be a contra‐indication for etidronate therapy;

• use of medications that might affect bone metabolism;

• associated health problems that could affect participation in the study or interfere with interpretation of the data, including active upper gastrointestinal, genitourinary, cardiovascular, liver, kidney or pulmonary disease.

Number screened: Not stated.

Number randomised: 89.

Number analysed: 88 (69 years, 67% male, percentages of monostotic and symptomatic participants not stated, 25% previously treated for Paget's disease of bone)

Interventions

Two parallel treatment groups: alendronate 40 mg (1 x etidronate placebo tablet and 1 x 40 mg alendronate tablet for 6 months) and etidronate 400 mg (1 x 400 mg etidronate tablet and 1 x alendronate placebo tablet for 6 months).

Co‐interventions: All participants received daily vitamin supplements containing 450 mg calcium carbonate and 400 IU vitamin D. Analgesics were available on demand and use was not balanced ("the regression analysis with adjustment for analgesics use at month 6 between the two treatment groups approached significance")

Outcomes

Outcomes reported in abstract

Primary endpoint: Mean percentage change from baseline in serum total alkaline phosphatase activity.

Secondary endpoints:

• mean percentage change from baseline in pain (measured using Brief Pain Inventory slightly modified for use in Paget's disease of bone);

• adverse events related to use of bisphosphonates;

• withdrawal due to adverse events;

• participants who normalised alkaline phosphatase level.

Time points for measurement: Baseline, 1 month, 3 months, 6 months.

How were the outcomes measured: prospectively

Setting and date

11 centres in USA.

Period when the study was conducted: Not reported

Follow up period

6 months

Publication details and funding source

Language of publication: English.
Publication status: peer‐reviewed journal; full article.

Funding source: Not reported.

Declarations of interest among primary researchers: Not reported

Notes

Transiliac bone biopsy was conducted for 43 participants at month 6. Bone biopsies were obtained from 25 healthy volunteers as control

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "the study was randomised".

Comment: insufficient information provided to permit judgement. Allocation was probably centralized because this was a multicentre study

Allocation concealment (selection bias)

Unclear risk

Insufficient information provided to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "The study was randomised and double blind", "The etidronate tablets were purchased as Didronel, crushed, and recompressed into tablets identical to placebo for etidronate".

Comment: Probably done.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Baseline and 6 months radiographs of one or more sites were read by one radiologist, who remained blind with respect to both treatment allocation and sequence of films". "Each specimen (bone biopsy) was blinded, so that the reader was unaware of the subjects' drug therapy."

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: Only one participant was excluded from the analysis (in the alendronate group). Reason for exclusion was reported.

The proportion of missing outcomes compared with observed event risk was insufficient to have a relevant impact of the effect estimate

Selective reporting (reporting bias)

Unclear risk

Methods and results sections were consistent. Insufficient information to permit judgement. We did not have access to a trial register record or study protocol to know if there was a prespecified record of the studies outcomes

Other bias

Unclear risk

There were differences between groups in co‐interventions because analgesics were taken on demand and use was not balanced. However this was thought unlikely to have resulted in bias. No other risks of bias found, but reporting was insufficient to permit judgement

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

Methods

RCT. Randomisation ratio: 1:1 (alendronate 40 mg: pamidronate 60 mg).

Superiority design

Participants

Diagnostic criteria: Paget's disease of bone was confirmed by the presence of typical lesions of Paget’s disease on isotope bone scanning and radiographs.

Inclusion criteria: Serum alkaline phosphatase above the upper limit of laboratory reference range.

Exclusion criteria:

• participants previously treated were excluded if < 3 months had elapsed since calcitonin treatment or < 6 months since bisphosphonate treatment, and if Paget’s disease of bone was in biochemical relapse, defined as plasma total alkaline phosphatase > 135 µ/L and at least 50% higher than the nadir value during previous treatment accompanied by radiological relapse of previously demonstrated lytic lesions.

• major comorbidity, untreated vitamin D deficiency, primary hyperparathyroidism, metabolic bone disease other than uncomplicated osteoporosis, recent partial or complete fracture through pagetic bone, clinically significant upper gastrointestinal disease, liver disease, and kidney impairment (plasma creatinine > 150 Amol/L).

Number screened: 139.

Number randomised: 72.

Number analysed: 72 (70 years, 58% male, % monostotic not stated, 94% symptomatic participants, 39% participants previously treated for Paget's disease of bone)

Interventions

Two parallel treatment groups: alendronate 40 mg daily in 3 months blocks and pamidronate four x 60 mg IV infusions a year (once every 3 months). Treatment was continued until biochemical remission was achieved or there were a no significant reduction on two consecutives measurements. Biochemical remission was defined as both, serum total alkaline phosphatase activity and urine deoxypyridinoline/creatinine ratio within the reference range.

Co‐interventions: All participants with plasma baseline total alkaline phosphatase > 675 U/L were prescribed ergocalciferol 30,000 U weekly for 3 months and calcium carbonate 600 mg daily for 8 months to minimize bisphosphonate‐induced secondary hyperparathyroidism. Other participants were treated with calcium and vitamin D supplements at the treating clinician’s discretion

Outcomes

Outcomes reported in abstract:

Primary endpoint: Proportion of participants achieving biochemical remission (see above).

Secondary endpoints: Numbers of participants; with change in bone pain (measured on VAS); with change on quality of life from baseline (assessed using the SF‐36 Australian version); who experienced severe side effects related to use of bisphosphonates; who withdrew due to adverse events, mean percentage change from baseline in serum total alkaline phosphatase activity; who normalised alkaline phosphatase level; and who relapsed due to recurrence of increased serum alkaline phosphatase level.

Time points for measurement: Baseline, 3, 6, 9, 12, 18 and 24 months.

How were the outcome measured: Prospectively

Setting and date

Three centres in Western Australia.

Period when the study was conducted: From May 1997 to October 2001

Follow up period

1 year without protocol amendment (2 year with protocol amendment)

Publication details and funding source

Language of publication: English.
Publication status: peer‐reviewed journal; full article.

Funding source: Although the authors described the trial as an "investigator‐initiated study", the study was supported by research grants from Merck, Sharp & Dohme (Australia), Novartis Pharmaceuticals Australia and the Arthritis Foundation of Western Australia.

Declarations of interest among primary researchers: Not stated

Notes

The initial protocol was amended to cross participants over from pamidronate to alendronate treatment at 12 months. According to the author, it was apparent that some participants randomised to pamidronate were showing little or no biochemical response to treatment and for "ethical" reasons, they amended the protocol so that participants randomised to pamidronate who did not achieve biochemical remission at 12 months were crossed over to alendronate treatment for the second year of the study.

We included data from the first year only in the meta‐analysis.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "To ensure that the two treatment groups were well matched, randomisation was stratified (using an in‐house computer program) by two variables: baseline plasma alkaline phosphatase (in three strata: 136–270, 271–675, > 675 U/L) and previous bisphosphonate treatment (as a binary variable: yes or no)." "In the course of the study, it was apparent that some patients randomised to pamidronate (predominantly in the previously treated subgroup) were showing little or no biochemical response to treatment. For ethical reasons, the protocol was amended so that patients randomised to pamidronate who did not achieve biochemical remission at 12 months were crossed over to alendronate treatment for the second year of the study".

Comment: The risk assessment was judged as low risk for first year data. For the second year, allocation was broken, and the risk of bias was assessed as high

Allocation concealment (selection bias)

Low risk

Authors describe using a computer program to generate the allocation

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open label trial

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Open label trial

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "Proportions of patients achieving remission for each treatment (on an intention to treat basis) were compared by Fisher’s exact test".

Comment: Data on screened participants, randomised participants and withdrawals (with reasons) are reported in a flow chart (Figure 1)

Selective reporting (reporting bias)

Unclear risk

Methods and results sections were consistent. Insufficient information to permit judgement. We did not have access to a trial register record or study protocol to know if there was a prespecified record of the studies outcomes

Other bias

Unclear risk

Likely high at 12 months due to amendment of the initial protocol. No other risks of bias found, but reporting was insufficient to permit judgement