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Cochrane Database of Systematic Reviews Protocol - Intervention

Strontium ranelate for osteoarthritis

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the benefits and harms of oral strontium ranelate to treat osteoarthritis.

Background

Description of the condition

Osteoarthritis is a common, age‐related, heterogeneous group of disorders characterised by focal areas of loss of articular cartilage in synovial joints, and structural changes such as subchondral bone remodelling and osteophytic formations (Dieppe 2005; Sarmanova 2016). Although osteoarthritis can affect any joint, the most commonly affected are the knees, hips, spine, and hands (Van der Kraan 2016).

Osteoarthritis is classified as either primary/idiopathic (cartilage degeneration with no underlying abnormality) or secondary (as a result of repetitive motion, trauma, inflammatory arthritis, or congenital abnormalities) (OARSI 2015).

Clinical manifestations of osteoarthritis include impaired mobility, as well as joint pain, inflammation, tenderness, stiffness, and crepitation (Van der Kraan 2016). Osteoarthritis is frequently associated with physical impairment and poor quality of life. In 2010, the estimated worldwide prevalence of radiographically confirmed and symptomatic knee and hip osteoarthritis was 3.8% and 0.85%, respectively (Cross 2014). The progressive and disabling nature of this disorder contributes significantly to the burden of disease for the individual person as well as for the health system. Among 291 clinical conditions included in the Global Disease Burden 2010 study, hip and knee osteoarthritis ranked 11th in terms of years lived with disability (YLDs) and 38th in terms of overall burden measured by disability‐adjusted life years (DALYs) (Cross 2014).

Description of the intervention

There are no established disease‐modifying treatments for osteoarthritis so far and the following modalities of interventions are currently used for patients with osteoarthritis.

Strontium ranelate is a long‐acting drug initially used to treat postmenopausal osteoporosis (Henrotin 2001; Gulhan 2008). For this purpose, it seems to reduce the relative risk of fractures (Reginster 2005). Additional post‐hoc analyses of an osteoporosis clinical trial showed that the participants in the strontium ranelate group had 15% to 20% lower levels of a urinary biomarker of cartilage degradation than those in the placebo group (Alexandersen 2007). A pooled analysis of two clinical trials suggested that a treatment of three years with strontium ranelate postponed the radiological progression of spinal osteoarthritis and relieved back pain when compared to placebo (Bruyere 2008).

Strontium ranelate (marketed as PROTELOS®, PROTOS®, OSSEOR®) is available in sachets that contain 2 g granules for oral suspension (682 mg of strontium). The proposed dose for osteoporosis is 2 g daily for a long‐term use. The overall half‐life of the drug is approximately 60 hours.

Strontium ranelate can produce serious adverse events including venous thromboembolism (VTE), myocardial infarction, Stevens‐Johnson syndrome, toxic epidermal necrolysis, and bone marrow failure. Common mild to moderate adverse events include gastrointestinal disorders (nauseas, vomiting, and diarrhoea), hypersensitivity skin reaction, and musculoskeletal pain (arthralgia, bone pain, muscle spasm, and myalgia) (EMA 2014).

The European Medicines Agency (EMA) approved strontium ranelate for osteoporosis in September 2004. Since then, the EMA Pharmacovigilance Risk Assessment Committee (PRAC) recommended restrictions due to reports of serious adverse events such as cardiovascular events (EMA 2014). The EMA has issued cautionary advice to doctors not to prescribe strontium ranelate for patients who have a history of or who are currently suffering from venous thromboembolism or for those who are bedridden for the short term or long term. Therefore the drug has been used with caution due to the positive benefit‐risk balance.

Despite the potential benefits of strontium ranelate for osteoarthritis, it has not been formally approved for this use so far, and it is currently used as an off‐label treatment.

How the intervention might work

Although the specific mechanism of action of strontium ranelate in osteoarthritis is still unclear, it could be related to its effects on bone metabolism. The positive impact of strontium ranelate on osteoarthritis seems to involve each of the following mechanisms.

  • Inhibition of subchondral bone resorption by controlling the activity of osteoprotegerin, RANK ligand, and matrix metalloproteinases produced by osteoblasts.

  • Direct action on cartilage, restoring the balance between catabolism and anabolism in tissues affected by osteoarthritis.

  • Stimulation of cartilage matrix formation by promoting the synthesis of proteoglycans" (Henrotin 2001 ; Tat 2011; Reginster 2013b).

Why it is important to do this review

There are several reasons why it is relevant to assess the effects of strontium ranelate for osteoarthritis to guide clinical practice, including the following.

  • The high and increasing worldwide prevalence of osteoarthritis.

  • The pain, physical disability, and poor quality of life associated with the progression of this disease.

  • The absence of a drug that can effectively relieve the symptoms of osteoarthritis and postpone the progression of the disease.

  • That strontium ranelate seems to be a promising drug for both clinical and radiographic improvement of osteoarthritis, but with restrictions regarding safety.

To the best of our knowledge, there are no previous systematic reviews on the effectiveness and safety of this intervention for people with osteoarthritis.

Objectives

To assess the benefits and harms of oral strontium ranelate to treat osteoarthritis.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs). We will include studies reported as full‐text articles, those published as abstracts only, and unpublished data. There will be no language restrictions. Given the progressive nature of the disease, we will not consider cross‐over trials.

Types of participants

Patients aged 18 or over, with bilateral or unilateral, primary or secondary osteoarthritis (osteoarthritis), in one or more joints, diagnosed according to the American College of Rheumatology criteria (Altman 1986), or with clinically or radiologically confirmed osteoarthritis. We will conduct a subgroup analysis considering different diagnosis criteria.

Types of interventions

Intervention

Oral strontium ranelate alone or associated with other medications at any dose and for any course duration. We will not include studies that assess multiple interventions where we cannot analyse the effect of strontium ranelate separately.

Comparators

  • No intervention.

  • Placebo.

  • Active pharmacological intervention (e.g. diacerein, glucosamine or chondroitin or both, collagen, herbal medication, or analgesics).

  • Active intra‐articular intervention (e.g. hyaluronic acid or corticosteroids).

  • Non‐pharmacological intervention (e.g. physical exercises, acupuncture, or physiotherapy).

Types of outcome measures

We will include studies that assess at least one of the following outcomes.

Major outcomes

  • Pain with a hierarchy of eight levels (when more than one is reported, we will consider the highest on the list).

    • Pain overall.

    • Pain on walking.

    • Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain subscale.

    • Pain on activities other than walking.

    • WOMAC global scale.

    • Lequesne osteoarthritis index global score.

    • Other algofunctional scale.

    • Patient’s global assessment.

    • Physician’s global assessment.

    • Other outcome.

    • No continuous outcome reported.

  • Physical function with a hierarchy of eight levels (when more than one is reported, we will consider the highest on the list).

    • Global disability score.

    • Walking disability.

    • WOMAC disability subscore.

    • Composite disability scores other than WOMAC.

    • Disability other than walking.

    • WOMAC global scale.

    • Lequesne osteoarthritis index global score.

    • Other algofunctional scale.

  • Radiographic joint structure changes according to the given hierarchy (when more than one is reported, we will consider the highest on the list).

    • Minimum joint space width.

    • Median joint space width.

    • Semi‐quantitative measurement.

  • Health‐related quality of life assessed by specific or generic validated tool, e.g. Health Assessment Questionnaire (HAQ) (Fries 1980), Short form 36 Health Survey (SF‐36) (Brazier 1992), EuroQoL; Sickness Impact Profile (SIP); Nottingham Health Profile (NHP) (Hunt 1981); other.

  • Proportion of participants who withdraw due to adverse events.

  • Proportion of participants who experience any adverse events.

  • Proportion of participants who experience serious adverse events (those that are immediately life‐threatening, or resulted in hospitalisation, incapacity, malignant disease, or death).

Minor outcomes

  • Participant global assessment of treatment success assessed by any validated tool. We will consider dichotomous, continuous, or Likert‐scale data. In this last case, we will dichotomise the categories.

Timing of outcome assessment

We will assess all outcomes listed above at any time point. However, we will only pool similar time points together: short term (up to three months, inclusive) or long term (more than three months).

Search methods for identification of studies

We will conduct a systematic search with no language or publication date restrictions, using the optimally sensitive strategy developed by Cochrane for the identification of RCTs.

Electronic searches

The Information Specialist of the Cochrane Musculoskeletal Group will conduct the searches of the following databases.

  • The Cochrane Central Register of Controlled Trials (CENTRAL).

  • Embase (Embase.com) (1974 to present).

  • MEDLINE (1966 to present).

  • Latin American and Caribbean Health Science Information Database (LILACS) (1982 to present).

  • Physioterapy Evidence Database (PEDro) (1999 to present).

  • ClinicalTrials.gov (www.clinicaltrials.gov).

  • World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (apps.who.int/trialsearch).

See Appendix 1 for the MEDLINE search strategy.

Searching other resources

The electronic literature search will be complemented by searching the additional sources.

  • Reference lists of all primary studies and review articles for additional references.

  • Relevant manufacturers' websites for trial information (and contact the organisation by phone or email).

  • We will contact experts and the main authors of included studies for additional unpublished or ongoing studies.

  • Abstract archives of annual meetings of the American College of Rheumatology (ACR) (www.rheumatology.org/Learning‐Center/Publications‐Communications/Abstract‐Archives).

  • Errata or retractions from included studies published in full‐text on PubMed (www.ncbi.nlm.nih.gov/pubmed). We will report the date we perform this in the review.

  • Abstract archives of annual meetings of the European League Against Rheumatism (EULAR) (www.eular.org/abstracts.cfm).

  • For assessments on adverse effects, we will search the websites of the following regulatory agencies: US Food and Drug Administration (FDA) MedWatch (www.fda.gov/Safety/MedWatch/default.htm), the European Medicines Agency (EMA) (www.ema.europa.eu/ema/), the Australian Adverse Drug Reactions Bulletin (http://www.tga.gov.au/) and the UK Medicines and Healthcare Products Regulatory Agency (MHRA) pharmacovigilance and drug safety updates (www.gov.uk/mhra)

Data collection and analysis

Selection of studies

Two review authors (RR and ALCM) will independently screen titles and abstracts of all potentially‐relevant studies identified by the searches, and code them as either 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'. We will retrieve the full‐text study reports/publication of the first group and two review authors (RR and ALCM) will independently read the full‐text articles and select those that fulfil the inclusion criteria. We will record the reasons for excluding ineligible studies. The two review authors will resolve any disagreement through discussion; if necessary, they will consult a third review author (VFMT). We will identify and exclude duplicates and collate multiple reports of the same study so that each study, rather than each report, is the unit of interest in the review. We will record the selection process in sufficient detail to complete a PRISMA flow diagram (Moher 2009; http://prisma‐statement.org/PRISMAStatement/Default.aspx) and a 'Characteristics of excluded studies' table.

Data extraction and management

Two review authors (RR and ALCM) will independently review the selected RCTs and will use a standard form to extract information on study characteristics and outcome data. We will extract the following information from the included studies.

  • Publication items (i.e. year, setting, country, authors).

  • Design and methods: criteria for inclusion/exclusion of participants, characteristics of the design of the trial as outlined below in the 'Assessment of risk of bias in included studies' section (details on allocation generation, allocation concealment, and blinding).

  • Participants' baseline characteristics (e.g. age, gender), severity of disease, type and anatomic site of osteoarthritis.

  • Intervention (dose, regimen, duration, co‐interventions).

  • Comparators (e.g. no intervention, placebo, active pharmacological intervention).

  • Outcomes (effectiveness and safety outcomes, time point of measures).

  • Dropouts (number and reasons).

  • Follow‐up (length).

  • Data analyses (i.e. per protocol, intention‐to‐treat, modified intention‐to‐treat).

  • Funding and conflict of interest disclosure.

  • Other potential risk of bias.

When necessary, we will discuss disagreements until we reach consensus and, if necessary, consult a third review author (VFMT) if necessary. Two review authors (RR and GJMP) will insert data into Review Manager (RevMan) (RevMan 2014). We will double‐check if the two review authors entered data properly into the software.

Assessment of risk of bias in included studies

Three review authors (RR, GJMP, and ALCM) will independently assess the quality of included RCTs using the criteria recommended by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011c), which consider seven domains for judging the risk of bias.

  • Sequence generation: was the allocation sequence adequately generated?

  • Allocation concealment: was allocation adequately concealed?

  • Blinding of participants and personnel: was knowledge of the allocated interventions adequately prevented during the study?

  • Blinding of outcome assessors: was knowledge of the allocated interventions adequately prevented during the study?

  • Incomplete outcome data: were outcome data adequately assessed and accounted for? (we will consider a loss to follow‐up rate greater than 15% as high risk).

  • Selective reporting: were the reports of the study free of any suggestion of selective outcome reporting?

  • Other potential threats to validity: was the study apparently free from other problems that could put it at risk of bias?

We will classify each domain as having a high, low, or unclear risk of bias and we will include a quote from the study report and the reason for our judgement in the 'Risk of bias' table.

We will summarise the 'Risk of bias' judgements across different studies for each of the domains listed. We will consider blinding separately for different key outcomes where necessary (e.g. for unblinded outcome assessment, risk of bias for all‐cause mortality may be different than for a patient‐reported pain scale). As well, we will consider the impact of missing data by key outcomes. Where information on risk of bias relates to unpublished data or correspondence with a trial author, we will note this in the 'Risk of bias' table. When considering treatment effects, we will take into account the risk of bias for the studies that contribute to that outcome. We will present the figures generated by the 'Risk of bias' tool to provide summary assessments of the risk of bias.

Assessment of bias in conducting the systematic review

We will conduct the review according to this published protocol and report any deviations from it in the 'Differences between protocol and review' section of the systematic review.

Measures of treatment effect

We will analyse dichotomous data as risk ratios or Peto odds ratios when the outcome is a rare event (approximately less than 10%), and use 95% confidence intervals (CIs). We will analyse continuous data as mean difference (MD) or standardised mean difference (SMD) values, depending on whether the same scale is used to measure an outcome, and 95% CIs. We will enter data presented as a scale with a consistent direction of effect across studies.

When the included studies use different scales to measure the same conceptual outcome (e.g. disability), we will calculate the SMD values instead, with corresponding 95% CIs. We will then back‐translate the SMDs to a typical scale (e.g. zero to 10 for pain) by multiplying the SMD by a typical among‐person standard deviation (SD) (e.g. the SD of the control group at baseline from the most representative trial) (Schünemann 2011b).

In the 'Effects of interventions' results section and the 'Comments' column of the 'Summary of findings' table, we will provide the absolute percent difference, the relative percent change from baseline, and the number needed to treat for an additional beneficial outcome (NNTB) or number needed to treat for an additional harmful outcome (NNTH). We will only provide the NNTB or NNTH value when the outcome shows a statistically significant difference.

For dichotomous outcomes, we will calculate the NNTB or NNTH from the control group event rate and the relative risk using the Visual Rx NNT calculator (Cates 2008). We will determine the NNTB or NNTH for continuous measures using the Wells calculator (available at the Cochrane Musculoskeletal Group editorial office).

For dichotomous outcomes, we will calculate the absolute risk difference using the risk difference statistic in RevMan (RevMan 2014), and will express the result as a percentage. For continuous outcomes, we will determine the absolute benefit as the improvement in the intervention group minus the improvement in the control group, in the original units, expressed as a percentage.

We will calculate the relative percent change for dichotomous data as the risk ratio ‐ 1 and expressed as a percentage. For continuous outcomes, we will determine the relative difference in the change from baseline as the absolute benefit divided by the baseline mean of the control group, expressed as a percentage.

Unit of analysis issues

The unit of analysis will be the individual.

Where multiple trial arms are reported in a single trial, we will include only the relevant trial arms. If two comparisons (e.g. drug A versus placebo and drug B versus placebo) are combined in the same meta‐analysis, we will halve the control group to avoid double‐counting. In this case, we will clearly state in the ‘Characteristics of included studies’ table that more than two intervention groups were present in the study.

Dealing with missing data

We will contact investigators or study sponsors in order to verify key study characteristics and obtain missing numerical outcome data where possible (e.g. when we identify a study as an abstract only or when data are unavailable for all participants). Where this is not possible, and the missing data are thought to introduce serious bias, we will explore the impact of including such studies in the overall assessment of results by a sensitivity analysis. We will clearly describe any assumptions and imputations to handle missing data and we will explore the effect of imputation by sensitivity analyses.

For dichotomous outcomes (e.g. number of withdrawals due to adverse events), we will calculate the withdrawal rate using the number of patients randomised in the group as the denominator.

For continuous outcomes (e.g. mean change in pain score), we will calculate the MD or SMD based on the number of patients analysed at that time point. If an included trial does not present the number of patients analysed for each time point, we will use the number of randomised patients in each group at baseline.

Where possible, we will compute the missing SD values from other statistics such as standard errors, CIs, or P values, according to the methods recommended in the Cochrane Handbook for Systematic Reviews of Interventions. If we cannot calculate SDs, we will impute these values (e.g. from other studies in the meta‐analysis) (Higgins 2011b).

Assessment of heterogeneity

We will assess clinical and methodological diversity in terms of participants, interventions, outcomes, and study characteristics for the included studies to determine whether a meta‐analysis is appropriate. We will conduct this by observing these data from the data extraction tables. We will assess statistical heterogeneity by visual inspection of the forest plot to assess for obvious differences in results between the studies, and using the I² and Chi² statistical tests.

As recommended in theCochrane Handbook for Systematic Reviews of Interventions (Deeks 2011), the interpretation of an I² statistic value of 0% to 40% might 'not be important'; 30% to 60% may represent 'moderate' heterogeneity; 50% to 90% may represent 'substantial' heterogeneity; and 75% to 100% represents 'considerable' heterogeneity. As noted in the Cochrane Handbook for Systematic Reviews of Interventions, we will keep in mind that the importance of I² statistic depends on: (i) magnitude and direction of effects and (ii) strength of evidence for heterogeneity.

We will interpret the Chi² test where a P value ≤ 0.10 indicates evidence of statistical heterogeneity.

If we identify substantial or considerable heterogeneity, we will report it and investigate possible causes by following the recommendations in Section 9.6 of the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2011). We will investigate possible causes of heterogeneity by subgroup and sensitivity analyses.

Assessment of reporting biases

We will create and examine a funnel plot to explore possible small study biases. In interpreting funnel plots, we will examine the different possible reasons for funnel plot asymmetry as outlined in Section 10.4 of the Cochrane Handbook and relate this to the results of the review. If we are able to pool more than 10 trials, we will undertake formal statistical tests to investigate funnel plot asymmetry, and will follow the recommendations in Section 10.4 of the Handbook (Sterne 2011).

To assess outcome reporting bias, we will check trial protocols against published reports. For studies published after 1 July 2005, we will screen the clinical trial register of the WHO ICTRP (http://apps.who.int/trialssearch) for the a priori trial protocol. We will evaluate whether selective reporting of outcomes is present.

Data synthesis

We will undertake meta‐analyses by using RevMan (RevMan 2014), and only where this is meaningful, i.e. if the treatments, participants, and the underlying clinical question are similar enough for pooling to make sense.

We will use a random‐effects model and perform a sensitivity analysis with fixed‐effect model.

We will restrict the primary analysis for self‐reported outcomes (e.g. outcomes such as pain, function, health‐related quality of life, the results that go in the 'Summary of findings' table and thus the Abstract and Plain Language Summary) to trials at low risk of detection and selection bias.

GRADE and 'Summary of findings' tables

We will create a 'Summary of findings' table using all the seven major outcomes stated under 'Types of outcome measures' and measured in long term (more than three months). Based on the relevance for clinical practice, we will consider the following comparisons for 'Summary of findings' table.

  • Strontium ranelate versus placebo/no intervention.

  • Strontium ranelate versus glucosamine sulphate.

  • Strontium ranelate versus chondroitin sulphate.

Two review authors (RR and ALCM) will independently assess the quality of the evidence. We will use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the quality of a body of evidence as it relates to the studies which contribute data to the meta‐analyses for the prespecified outcomes, and report the quality of evidence as either high, moderate, low, or very low. We will consider the following criteria for upgrading the quality of evidence, if appropriate: large effect, dose‐response gradient, and plausible confounding effect. We will use methods and recommendations described in Section 8.5 and 8.7, and Chapters 11 and 12, of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a; Schünemann 2011a; Schünemann 2011b). We will use GRADEpro software to prepare the 'Summary of findings' tables (GRADEpro GDT 2014). We will justify all decisions to downgrade or upgrade the quality of the evidence using footnotes and we will make comments to aid the reader's understanding of the review where necessary. We will provide the number needed to treat for an additional beneficial outcome (NNTB) or the number needed to treat for an additional harmful outcome (NNTH), absolute and relative percent change in the Comments column of the 'Summary of findings' table as described in the 'Measures of treatment effect' section above.

Subgroup analysis and investigation of heterogeneity

We plan to perform the following subgroup analyses.

  • Different doses of strontium ranelate (2 g/day (usual dose), less than 2 g daily, more than 2 g/day).

  • Different joints (e.g. shoulder, hip, knee, spine, hands).

  • Severity of disease (i.e. Kellgreen‐Lawrence scale for knee, I, II, III, and IV) (Kellgren 1957).

  • Sedentary or physically active participant (participants will be considered sedentary if they did not practice any type of physical exercise during the last three months; those who did will be considered physically active).

  • Different time points: short term (up to three months, inclusive) or long term (more than three months).

  • Participants with a history of, or those who are currently suffering from VTE, or those who are bedridden for the short term or long term versus those without these characteristics.

We will use the following outcomes in subgroup analyses.

  • Pain.

  • Physical function.

  • Proportion of patients experiencing a serious adverse event.

We will use the formal test for subgroup interactions in RevMan (RevMan 2014), and will use caution in the interpretation of subgroup analyses as advised in Section 9.6 of the Cochrane Handbook for Systematic Reviews of Interventions. We will compare the magnitude of the effects between the subgroups by assessing the overlap of the CIs of the summary estimate. Non‐overlap of the CIs indicates statistical significance.

Sensitivity analysis

We will use sensitivity analyses to determine the robustness of the review findings. We plan to undertake the following sensitivity analyses for the primary outcome overall pain.

  • Inclusion of all trials regardless of the risk of bias for detection and selection bias.

  • Random‐effects model versus fixed‐effect model.

Interpreting results and reaching conclusions

We will follow the guidelines in Schünemann 2011b for interpreting results, and will be aware of distinguishing between lack of evidence of effect and lack of effect. We will base our conclusions only on findings from the quantitative or narrative synthesis of included studies for this review. We will avoid making recommendations for practice, and our implications for research will suggest priorities for future research and outline what the remaining uncertainties are in the area.