Aminobisphosphonates versus other active treatment for Paget's disease of the bone in adults
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To compare aminobisphosphonate therapy with other active treatments for adult patients with Paget's disease of the bone.
Background
Paget's Disease of bone (PDB) is a common metabolic bone disease, which is second in prevalence only to osteoporosis (brittle bone disease) in people of European descent. In the UK, it affects up to 3% of the population above the age of 55 years (Cooper 1999), and increases in prevalence with age, affecting 8% of men and 5% of women by their 8th decade (van Staa 2002). The overall prevalence of PDB in those over the age of 55 years in the UK has fallen from 5% to 3% over the last 25 years (Barker 1980; Cooper 1999), and, although a similar decrease in prevalence has been reported in New Zealand (Cundy 1997), no change in prevalence has been observed in the USA (Tiegs 2000).
Characterised by focal increases in bone turnover (points at which the disease/turnover is concentrated), PDB is a cause of substantial morbidity (ill health), causing such diverse symptoms as bone pain, pathological fracture (fracture arising from disease), deafness, bone deformity, and secondary osteoarthritis. It may affect just one bone (monostotic) or many bones (polyostotic) in the skeleton. Patients with PDB run a significantly increased risk of developing osteoarthritis (van Staa 2002), and their need for hip replacement is substantially higher than that of age‐matched controls (van Staa 2002). Osteosarcoma (malignant bone tumour) is a rare complication, however, virtually all osteosarcomas found in adults over the age of 60 years occur in patients with PDB (Sandberg 2003). Other complications of PDB include spinal stenosis (narrowing of the spine), internal hydrocephalus (raised pressure within the brain), basilar impression (compression at the base of the skull affecting the spinal cord and blood flow to the brain), cranial nerve deficits and other nerve compression syndromes (Selby 2002).
Medical therapy for PDB is based on drugs that inhibit the increased osteoclastic bone resorption (dissolution of bone by osteoclast cells), that characterises Paget's disease, and reduce the increase in bone turnover that is associated with the disease (indicated by biomarkers of bone resorption and formation of compounds such as urinary hydroxyproline and serum alkaline phosphatase). Many types of drug have been shown to be effective for Paget's disease, and, although salmon calcitonin (a hormone that lowers the levels of calcium and phosphate in the blood) is still occasionally used, bisphosphonates (which block the action of the osteoclast cells that resorb calcified bone) are the most widely used antiresorptive agents.
Bisphosphonates have a common phosphorous‐carbon‐phosphorous core, to which various chemical side‐chains are attached. The nature of these side‐chains has a profound effect on the antiresorptive potency of the bisphosphonate, and on the mechanism by which osteoclast inhibition occurs. Simple bisphosphonates, such as etidronate, clodronate and tiludronate, are relatively weak antiresorptive agents that work by incorporating non‐hydrolysable analogues of adenosine triphosphate (ATP) (i.e. forming molecules that mimic ATP ‐ the cells' energy source ‐ but cannot be used for energy), thereby depleting intracellular energy stores and promoting apoptosis (cell death) (Frith 2001). Bisphosphonates that contain a nitrogen atom in the side chain (aminobisphosphonates) are much more potent and act by inhibiting the enzyme farnesyl pyrophosphate (FPP) synthase. Aminobisphosphonate‐mediated inhibition of this enzyme disrupts signalling pathways in osteoclasts, leading to failure of their resorptive function and cell death. Salmon calcitonin and oral bisphosphonate disodium etidronate have been shown to reduce abnormal bone turnover by approximately 50% ‐ a reduction that is clinically beneficial in most patients (Altman 1973; Fleisch 1987; Siris 1996b). More recently, potent aminobisphosphonates, such as intravenous pamidronate, alendronate and risedronate, have been shown to reduce abnormal bone turnover to normal levels (Miller 1999; Siris 1996a), with associated relief from symptoms, and the possibility of reducing long term complications of the disease such as the progression of deafness. Frequently, treated patients also display clinical improvement of bone pain, with bone biopsy specimens showing that the architecture of newly formed bone appears more normal (Siris 1996b). These drugs also allow the dose to be tailored to match the severity of patients' disease (Siris 1996b).
However, these potent aminobisphosphonates are more expensive than simple bisphosphonates, with a standard course of oral risedronate (30 mg daily for two months) costing £306, in comparison to a course of etidronate (400 mg daily for six months) at £263 (BNF March 2003). It should be borne in mind that one course of these newer aminobisphosphonates may induce a longer remission period, and that, as a consequence, they may be as cost‐effective as non‐aminobisphosphonates. Nonetheless, all bisphosphonates, by virtue of their mode of action, have the potential to induce focal osteomalacia (softening of the bones caused by a deficiency of vitamin D) (Boyce 1984; Fleisch 1987), and there is concern about this and other side effects (for example gastro‐intestinal side‐effects) associated with the use of aminobisphosphonates.
With an increasing number of active treatments available to clinicians, our goal is to review the evidence for aminobisphosphonate therapy for Paget's disease of the bone against other active treatments (not placebo).
Objectives
To compare aminobisphosphonate therapy with other active treatments for adult patients with Paget's disease of the bone.
Methods
Criteria for considering studies for this review
Types of studies
All published and unpublished randomised controlled trials and quasi‐randomised controlled trials that compare aminobisphosphonate therapy with other active treatment(s) for the management of Paget's disease of the bone in adults will be included. Trials must be of at least three months' duration.
Types of participants
Adults with Paget's disease of the bone (diagnosed by standard clinical, radiographic, scintigraphic and biochemical criteria) will be included.
Types of interventions
Trials comparing oral or intravenous aminobisphosphonates (e.g. zolendronic acid, risedronate sodium, disodium pamidronate, alendronic acid, ibandronate sodium) versus other active treatments (e.g. etidronate, tiludronate, calcitonins, etc.) for Paget's disease of the bone will be eligible for inclusion. At least one arm of included studies must use an aminobisphosphonate and at least one other arm must use another active treatment. Trials comparing an aminobisphosphonate against placebo only will not be included. Interventions must be of at least three months' duration.
Types of outcome measures
Primary outcome measures:
1. Number of participants with improved bone pain;
2. Number of participants experiencing adverse events (e.g. gastro‐intestinal side effects, fever).
Secondary outcome measures:
1. Number of participants experiencing fractures;
2. Mean reduction of serum alkaline phosphatase level;
3. Number of patients that relapse (due to recurrence of bone pain);
4. Number of patients that relapse (due to recurrence of increased serum alkaline phosphatase levels);
5. Quality of life, including:
a. Generic quality of life (e.g. SF36, EQ5D);
b. Arthritis‐specific quality of life (e.g. ASHI, HAQ).
If data permit, outcomes will be analysed for each treatment at the following time points:
three months, six months, one year, and two years from the start of treatment, and at the end of the trial.
Search methods for identification of studies
A number of databases will be searched for relevant trials using the search strategies detailed in the appendices:
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The Cochrane Central Register of Controlled Trials (CENTRAL): Appendix 1
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MEDLINE (1966‐2004): Appendix 2
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EMBASE (1980‐2004): Appendix 3
Additional trials will be sought in the reference lists of relevant articles. No language or other limitations will be imposed.
Data collection and analysis
Selection of trials
All abstracts identified by the above search strategy will be assessed for subject relevance by two researchers (AL, CR). The full publications of all potentially relevant abstracts will be obtained and formally assessed for inclusion. A data abstraction form will be developed to record details of study design, participants, setting and timing, interventions, patient characteristics, and outcomes.
Quality of trials
All potentially eligible studies will be evaluated for methodological quality by two of the reviewers, independently, without prior consideration of the results. Each reviewer will undertake assessment of methodological quality using the Musculoskeletal Group's assessment criteria, which will include quality of random allocation and concealment, description of dropouts and withdrawals, analysis by intention to treat, and blinding during treatment and at outcome assessment. Any differences of opinion will be resolved by discussion with the third reviewer (MKC).
Data extraction
Data extraction will be performed independently on included studies by two reviewers (AL, CR) and cross‐checked. Where a difference of opinion exists, the two reviewers will consult a third reviewer (MKC). Where data may have been collected but not reported, clarification will be sought from the trialists. Data will be extracted using a pre‐developed form and entered into RevMan 4.2 by one reviewer and checked by another reviewer.
Statistical analysis
The review will be conducted using the standard Cochrane software, RevMan. Quantitative synthesis is planned if more than one eligible study is identified. Where appropriate, a pooled estimate of treatment effect across similar studies will be calculated for each pre‐specified outcome. Dichotomous outcome data will be reported as relative risks (RR) and numbers needed to treat (NNT), while continuous outcomes will be reported as weighted mean differences (WMD) and absolute changes. Where possible, 95% confidence intervals will be generated. A fixed effect approach to the analysis will be undertaken unless there is evidence of heterogeneity across studies. Evidence of heterogeneity will be determined by visual inspection of the data, or from the chi‐squared and I‐squared tests for heterogeneity. If evidence of significant heterogeneity is identified, potential sources of heterogeneity will be explored within populations, interventions, outcomes and settings, and a random effects approach to the analysis undertaken. A narrative review of eligible studies will be undertaken where statistical synthesis of data from more than one study is not possible or appropriate.
If the data permit, sub‐group analyses will consider differences with the extent of skeletal involvement of PDB (monostotic/polyostotic), dose of treatment, and class of bisphosphonate therapy.
Grading of evidence
We will use the grading system described in the 2004 book Evidence‐based Rheumatology (Tugwell 2004) and recommended by the Musculoskeletal Group:
Platinum: A published systematic review that has at least two individual controlled trials each satisfying the following :
·Sample sizes of at least 50 per group ‐ if these do not find a statistically significant difference, they are adequately powered for a 20% relative difference in the relevant outcome.
·Blinding of patients and assessors for outcomes.
·Handling of withdrawals >80% follow up (imputations based on methods such as Last Observation Carried Forward (LOCF) are acceptable).
·Concealment of treatment allocation.
Gold: At least one randomised clinical trial meeting all of the following criteria for the major outcome(s) as reported:
·Sample sizes of at least 50 per group ‐ if these do not find a statistically significant difference, they are adequately powered for a 20% relative difference in the relevant outcome.
·Blinding of patients and assessors for outcomes.
·Handling of withdrawals > 80% follow up (imputations based on methods such as LOCF are acceptable).
·Concealment of treatment allocation.
Silver: A systematic review or randomised trial that does not meet the above criteria. Silver ranking would also include evidence from at least one study of non‐randomised cohorts that did and did not receive the therapy, or evidence from at least one high quality case‐control study. A randomised trial with a 'head‐to‐head' comparison of agents would be considered silver level ranking unless a reference were provided to a comparison of one of the agents to placebo showing at least a 20% relative difference.
Bronze: The bronze ranking is given to evidence if at least one high quality case series without controls (including simple before/after studies in which patients act as their own control) or if the conclusion is derived from expert opinion based on clinical experience without reference to any of the foregoing (for example, argument from physiology, bench research or first principles).
Clinical relevance tables
Clinical relevance tables will be compiled under additional tables to improve the readability of the review. For dichotomous outcomes, like complications, the number needed to treat will be calculated from the control group event rate and the relative risk using the Visual Rx NNT calculator (Cates 2003). Continuous outcome tables will also be presented under additional tables. Absolute benefit will be calculated as the improvement in the intervention group minus the improvement in the control group, in the original units. Relative difference in the change from baseline will be calculated as the absolute benefit divided by the baseline mean of the control group.
