Conservative treatment for osteoarthritis of the ankle

  • Protocol
  • Intervention



This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the benefits and harms of any conservative treatment for ankle OA in adults in order to provide a synthesis of the evidence as a base for future treatment guidelines.


Description of the condition

Osteoarthritis (OA) is a chronic and degenerative disorder associated with joint pain and loss of joint function. OA can affect any synovial joint but is found most frequently in the hip, knee and hand, the majority of these patients present with primary OA (idiopathic disease) (Buckwalter 2004; Kalunian 2012; Witteveen 2008). Reliable figures on the prevalence of OA in other joints are not readily available but estimates suggest that the incidence of symptomatic ankle OA is 1% to 4% in the adult population (Cushnaghan 1991; Peyron 1984). In contrast to knee and hip OA, 70% to 78% of patients with ankle OA present  themselves with secondary, post-traumatic disease, the remainder is primary OA as well as inflammatory diseases, such as rheumatoid arthritis and gout (Saltzman 2005; Valderrabano 2009). Ankle trauma occurs in many patients at a relatively young age (Agel 2005; Saltzman 2005). Consequently, the expected life span of many patients with ankle OA is significantly longer than the life span of hip or knee OA patients; this affects their quality of life for a substantial amount, Saltzman 2006 demonstrated that the self reported physical function in patients with symptomatic ankle OA quantified using the Short Form-36 (SF-36) questionnaire was equivalent to or worse than that of patients with end-stage kidney disease or congestive heart failure suggesting that these patients are seriously impaired.

Description of the intervention

In clinical practice, patients diagnosed with end-stage OA (Kellgren Lawrence 3 or 4 and van Dijk 3) are offered operative treatment if they have significant clinical symptoms (Harada 2011; van Dijk 1997).These patients are treated by arthrodesis, ankle replacement or osteotomy. Surgical treatment is specifically reserved for end stage arthritis. It is considered to be harmful due to short and long term complications. Complications consist of wound healing problems, infectious disease, non or delayed union and OA of adjacent joints due to overloading (Chang 2013; Deorio 2008; Jung 2007; Krause 2012; Rippstein 2012; Suckel 2012). Operative treatment is therefore not considered in an early phase of OA, it remains a challenge to treat patients that are diagnosed with a low grade OA of the ankle (Kellgren Lawrence 1, 2 or 3 and Van Dijk 1 or 2) (Harada 2011; van Dijk 1997). They are young and they experience serious disabilities which prevent these patients from participating in more heavily laboured work as well as sports activities. Several conservative treatment options are available, however evidence of the benefits and harms of these options are lacking.

The conservative treatment of symptomatic ankle OA, like general OA, consists mainly of treating symptoms like pain and stiffness. Since no cure is available at this point another treatment goal is preventing deterioration of the joint (Towheed 2006). Non-pharmacological therapy is to be considered the foundation for the successful medical management of general OA (Hochberg 2012; Zhang 2008; Zhang 2010).There are systematic reviews published for knee and hip OA and include weight reduction (BMI > 25), physiotherapy and occupational therapy (Brosseau 2011; Brouwer 2005; Rutjes 2009; Rutjes 2010). For ankle OA offloading the joint by brace, cane, rocker sole or inlay can reduce the pain as well (Bartels 2007; Brosseau 2003; Fransen 2009; Janisse 1998; Kempson 1991; Messier 2005; McGuire 2003; Wu 2004). If this is not successful a painkiller can be added. In case of pain relief several options are available, e.g. painkillers like acetaminophen, opioids and non-steroidal anti-inflammatory drugs (NSAIDs) (Cepeda 2006; Garner 2005; Nuesch 2010; Towheed 2006). Hyaluronic acid has been shown to reduce pain as well (Chang 2013; Cohen 2008; Pleimann 2002; Salk 2006; Sun 2006; Witteveen 2008; Witteveen 2010). The benefit of glucosamine/chondroitin for pain reduction in general OA was not shown (Towheed 2005).

How the intervention might work

Ankle OA pain can be reduced by off loading the joint through rest, wearing a brace or using a cane. A cane can reduce the amount of bodyweight going through the ankle joint by 25% (Kempson 1991). Rockersoles are thought to off load the ankle joint  by decreasing the ankle motion at heel strike to push off during walking (Wu 2004). Weight loss by dietary adjustments or exercises are thought to off load a joint as well (Bartels 2007; Brosseau 2003; Fransen 2009). In Messier 2005, each pound of weight loss  created a 4-fold reduction in the load exerted by step at the knee during daily activities. Shoe adjustment like inlays can correct alignment issues and in this way off load a part of the joint thus creating pain reduction (Janisse 1998; McGuire 2003). It is possible that in this way the joint can be preserved from further deteriorating. Several analgesics are available like acetaminophen, opioids and NSAIDs. They either act as a simple analgesic, have anti inflammatory effects, a sedative effect or a combination. Recommendations for hip, knee or hand OA are well described (Hochberg 2012). Hyaluronic acid (visco supplementation) is thought to restore rheologic properties of the joint by creating a more viscoelastic synovial fluid which improves mobility and restores the natural protective function of the joint, like shock absorption during gait (Balazs 1993; Bellamy 2006). Several studies have shown pain reduction as well (Chang 2013; Cohen 2008; Pleimann 2002; Salk 2006; Sun 2006; Witteveen 2008; Witteveen 2010). Glucosamine/chondroitine may be potentially chondro protective and may modify the progression and course of general OA. However, up until now no evidence has been found to prove this theory (Towheed 2005).    

Why it is important to do this review

Lots of treatment modalities are offered, however no clear cut treatment algorithm for ankle OA is used. The choice of treatment depends on the severity of the disease, the patients' age, medical and social history and the level of physical activity expected to be demanded of the joint. For knee and hip OA several treatment algorithms are advocated (Kalunian 2012; Pendleton 2000; Tannenbaum 2000; Towheed 2005; Towheed 2006; Zhang 2008; Zhang 2010). However, since ankle OA may be caused by a different mechanism, it is not unthinkable that these patients need a different treatment.

At this point there is no evidence based treatment algorithm for ankle OA. Several papers have been published concerning the cause of ankle OA and the possible conservative and operative treatment strategies. The conservative section mainly sums up the possibilities, however no algorithm is suggested (Demetriades 1998; Katcherian 1998; Martin 2007; Rao 2010; Rhys 2003).This review will be conducted to find evidence for the benefits and harms of non-pharmacological and pharmacological treatment of ankle OA in general or by stage of the disease. We will try to provide a synthesis of the evidence as a base for future treatment guidelines. 


To assess the benefits and harms of any conservative treatment for ankle OA in adults in order to provide a synthesis of the evidence as a base for future treatment guidelines.


Criteria for considering studies for this review

Types of studies

All randomised controlled trials (RCTs) and controlled clinical trials (CCTs) will be included in this review.                   

Types of participants

Adults with the diagnosis of symptomatic ankle OA (primary or secondary) will be included in this review. The diagnosis must be based on well described clinical criteria e.g. the American College of Rheumatology (ACR) criteria (Hochberg 2012), or based on a previously taken X-ray, which is classified using either the Kellgren Lawrence or the Van Dijk scale (Harada 2011; van Dijk 1997).

Types of interventions

Trials investigating any non-surgical intervention are eligible.

We will include:

  • pharmacologic therapy: analgesics; acetaminophen, opioid analgesics like codeine, oxycodone or tramadol, NSAIDs like ibuprofen or celecoxib, intra-articular glucocorticoids, intra-articular hyaluronans, glucosamine and chondroitin;

  • non-pharmacologic therapy such as weight loss, rest, physical therapy and orthoses: braces, taping, insoles, exercise (strengthening, mobility, endurance and joint stability), manual therapy, diet, self management, psychosocial interventions (Kalunian 2012).

We will exclude other methods including traditional medicine (e.g. herbs, acupuncture) and naturopathies.

We will identify two special types of RCTs or CCTs:

  • RCTs or CCTs that compare a treatment/therapy alone to placebo; and

  • RCTs or CCTs that compare one treatment to the other.

Types of outcome measures

  • Pain with a hierarchy of seven levels:

    • pain of the affected joint;

    • pain on walking;

    • pain on actIvitIes other than walking;

    • rest pain or pain during the night;

    • other algofunctional scale;

    • patient's global assessment;

    • physician's global assessment.

 When more than one is reported, the highest on the list will be taken.

  • Physical function with a hierarchy of eight levels:

    • global disability score;

    • walking disability;

    • disability other than walking;

    • American Orthopedic Foot and Ankle Society score (AOFAS score);

    • Foot and Ankle Outcome Score (FAOS);

    • Foot Function Index (FFI);

    • Function (Range of Motion (ROM));

    • other algofunctional scale.

When more than one is reported the highest on the list will be taken.

  • Radiographic joint structure changes according to the given hierarchy:

  • Quality of Life:

    • Short Form-36 (SF-36)

    • EuroQoL-5 Dimensions (EQ-5D).

  • Patients experiencing any serious adverse events

  • Number of patients experiencing any adverse event

  • Patients who withdraw because of an adverse event or any other reason

If pain or function outcomes are reported at several time-points, the end of treatment will be taken as primary time-point for pharmacologic treatment such as acetaminophen, opioids or NSAIDs, with the three months interval as an additional time-point.

In case of hyaluronans, glucocorticoids, glucosamine and chrondoitin and nonpharmacologic therapy, six months will be considered as primary time-point and the three months interval as an additional time-point.

Search methods for identification of studies

Electronic searches

We will search the following electronic databases, unrestricted by date ( from inception onwards) or language:

  • MEDLINE (Ovid) (Appendix 1);

  • Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library) (Appendix 2);

  • EMBASE (Ovid) (Appendix 3);

  • PsycINFO (American Psychological Association) (Appendix 4);

  • CINAHL (Cumalitive Index to Nursing and Allied Health Literature) (EBSCO) (Appendix 5);

  • PEDro (Physiotherapy Evidence Database) (Appendix 6);

  • AMED (Allied and Alternative Medicine) (Ovid) (Appendix 7).

Searching other resources

We will search the following clinical trial registries to identify ongoing trials:

We will also screen reference lists in retrieved review articles and trials to identify potentially relevant studies.

Data collection and analysis

Selection of studies

Two authors (AW, CH) will independently screen records identified from database searches for possible inclusion. Full-text articles will be retrieved for further assessment when the initial information appears to align with the review criteria. Trials not fulfilling the outlined selection criteria will be excluded. Reasons for exclusion will be documented. A third author (GK) will moderate any disagreement.

Data extraction and management

Data extraction of the included studies will be completed by two authors (AW, GK), and recorded on a data extraction form. Disagreements will be resolved by discussion amongst the other authors.

We will collect data on study design characteristics, descriptive characteristics of the participants, interventions, outcome measures, and length of follow-up. We will contact trialists for clarification when necessary. 

The data extraction form will include the following

  • Generic publication characteristics:

    • type of publication;

    • title;

    • authors;

    • year of publication.

  • Research design:

    • randomised controlled study / controlled clinical trial;

    • blinding of outcome assessors;

    • allocation concealment.

  • Descriptive characteristics of participants:

    • number of participants;

    • age;

    • sex;

    • duration of ankle OA;

    • grade of ankle OA;

    • baseline measures;

    • diagnoses; inclusion and exclusion criteria;

    • if applicable, randomisation outcomes such as numbers allocated to each group at baseline, withdrawals, intention-to-treat numbers, and losses to follow-up.

  • Intervention characteristics:

    • non-surgical intervention: analgesics; acetaminophen, opioid analgesics like codeine, oxycodone or tramadol, NSAIDs such as ibuprofen or celecoxib, intra-articular glucocorticoids, intra-articular hyaluronans, glucosamine and chondroitin;

    • non-pharmacologic therapy: weight loss, rest, physical therapy and orthoses: braces, taping, insoles, exercise (strenghtening, mobility, endurance and joint stability), manual therapy, diet, self management, psychosocial interventions;

    • comparative intervention;

    • duration of the intervention (duration (weeks/months) and frequency);

    • follow-up.

  • Outcomes (benefits and harms):

    • pain;

    • safety;

    • quality of Life;

    • physical function.

Disagreements in data extraction will be resolved via discussion and further scrutiny of the original data.

Assessment of risk of bias in included studies

For assessment of risk of bias in the selected studies we will use the Cochrane Collaboration's tool for assessing risk of bias (Higgins 2011). Two authors (AW, AD) will independently assess generation of allocation sequence, allocation concealment, blinding, incomplete outcome data, selective outcome reporting (reporting bias), and other sources of bias (baseline imbalance in factors which are strongly related to outcome measures e.g. grade of ankle OA; Intervention characteristics e.g. dosage of medication, frequency of therapy).

Bias will be judged as 'high risk' of bias, 'low risk' of bias, or 'unclear' risk of bias. We will resolve disagreements by consensus or discussion with a third author (CH).

Measures of treatment effect

To assess intervention efficacy and safety, we will present the mean differences (MDs) or standardised mean differences (SMDs), and 95% confidence intervals (CIs) for continuous outcomes; and risk ratios (RRs) and 95% CIs for dichotomous outcomes.

Unit of analysis issues

The unit of analysis will be the participant. If we identify RCTs or CCTs that treat both ankles, and the number of ankles is used as the denominator in the analysis without adjustment for the non-independence between ankles (and thus may have potential unit of analysis errors), we will attempt to re-analyse such studies by calculating sample sizes where possible, according to the methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). If it is stated in the article that more than 10% of the patients suffer from general OA, the treatment effect of any treatment for ankle OA will be very difficult to interpret therefore these studies will be excluded.

Dealing with missing data

Where data cannot be directly extracted, we will contact the trialists, or missing data will be imputed by imputing the missing data with replacement values, and treating these as if they were observed (last observation carried forward) (Higgins 2011). If we impute data, we will note so in the table 'Characteristics of included studies'.

Assessment of heterogeneity

We will test heterogeneity of the data using the Chi2 with a P value < 0.10 indicating significant heterogeneity. We will assess the I2 statistic to quantify inconsistency across the results (Higgins 2011) (I2 = [Q df / Q] x 100%; where Q is the Chi2 statistic and df is the degrees of freedom). A value greater than 50% may indicate substantial heterogeneity. In the case of substantial heterogeneity, data will be explored further, including subgroup analyses, in an attempt to explain the heterogeneity. Beside this procedure, we will also perform a visual assessment of forest plots to assess heterogeneity (Higgins 2011).

Assessment of reporting biases

We expect a low number of eligible studies however in the event of a relatively large number of studies meeting the inclusion criteria, funnel plots (produced in RevMan5) will be used to review publication bias. Treatment effects will be plotted against standard error. Two authors (CH, AD) will visually inspect the funnel plot for asymmetry. Where disagreement exists, a third author (AW) will be consulted.

We will also investigate selective outcome reporting by comparing the study outcomes with those routinely presented for similar studies and also by comparing the methods section of trial reports with the results reported. 

Data synthesis

If sufficient data is present we will pool results of comparable groups of trials. Initially we will use the fixed-effect model and 95% CIs. A fixed-effect meta-analysis provides a result that may be viewed as a 'typical intervention effect' from the studies included in the analysis. In order to calculate a confidence interval for a fixed-effect meta-analysis the assumption is made that the true effect of intervention (in both magnitude and direction) is the same value in every study (that is, fixed across studies). This assumption implies that the observed differences among study results are due solely to the play of chance, i.e. that there is no statistical heterogeneity (Higgins 2011). We will also consider using the random-effects model, especially where there is unexplained heterogeneity ( Higgins 2011). We will use the Cochrane Collaboration's statistical software, Review Manager 2013, for data synthesis.

Subgroup analysis and investigation of heterogeneity

We expect that, due to the lack of data, we are not able to perform a subgroup analysis. If nonetheless sufficient data will be present. We will try to analyse if there is a difference between the benefits and harms of conservative treatments for each grade of OA of the Kellgren Lawrence score (grade 1, 2, or 3) or the van Dijk score (grade 1 or 2).

Sensitivity analysis

Where possible, the review authors will perform sensitivity analyses to examine the effects of important sources of bias, such as whether allocation was concealed, if blinding has been performed properly and if an intention to treat analysis has been performed in case of drop out. We will also perform a sensitivity analysis to investigate the possible impact of missing data on the findings of the review.

Summary of findings table

The main findings of the study will be presented in a "Summary of finding" table, which will be produced using GRADEpro software (GRADEprofiler 2008). This table will provide key information concerning the quality of the evidence, the magnitude of effect of the interventions examined, and the sum of available data on the main outcomes. The table will include an overall grading of the evidence related to each of the main outcomes using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, as indicated in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). If we find more than one main comparison we will provide separate  "Summary of findings" tables for each comparison. The important outcomes that could be included in the "Summary of findings" tables are:

  1. pain;

  2. physical Function;

  3. radiographic joint structures changes;

  4. quality of life;

  5. number of patients experiencing any serious adverse events;

  6. number of patients experiencing any adverse event;

  7. patients who withdraw because of an adverse event or any other reason.


We like to thank Elizabeth Ghogomu and the editorial team of the Cochrane review group for their contributions.


Appendix 1. MEDLINE search strategy

Search terms for design 

1     randomized controlled

2     controlled clinical

3     randomized.ab.

4     placebo.ab.

5     clinical trials as

6     randomly.ab.

7     trial.ti.

8     or/1-7

9     exp animals/ not

10     8 not 9 

Search terms for population 

11    Ankle/ or Ankle Joint/


13     exp Osteoarthritis/

14     exp Arthritis/

15     (osteoarthritis or arthritis or arthrosis or osteoarthrosis or (degenerative adj (arthr$ or disease))).af.

16     11 or 12

17     13 or 14 or 15

18     16 and 17 

Combining terms 

19     10 and 18

Appendix 2. CENTRAL search strategy

 1 MeSH descriptor Osteoarthritis explode all trees

2 MeSH descriptor arthritis explode all trees

3 (osteoarthritis OR arthritis OR arthrosis OR osteoarthrosis OR (degenerative near/3 (arthr* OR disease)))

4 MESH descriptor ankle OR MESH descriptor ankle joint

5 ankle

6 (#1 OR #2 OR #3)

7 (#4 OR #5)

8 (#6 AND #7) 

Appendix 3. EMBASE search strategy

Search terms for design 

1     randomized controlled


3     exp clinical trials/

3     (clin$ adj25 trial$).ti.ab

4     random$.ti.ab.

5    or/1-4

Search terms for population 

6    Ankle/ or Ankle Joint/


8     exp Osteoarthritis/

9    exp Arthritis/

10  (osteoarthritis or arthritis or arthrosis or osteoarthrosis or (degenerative adj3 (arthr$ or disease))).ti.ab.

11     6 or 7

12    8 or 9 or 10

13    11 and 12 

Combining terms 

14     5 and 13 

Appendix 4. PsycINFO search strategy

Search terms for design 

1     clinical or exp Clinical Trials 

2     randomized controlled

3     clinical trial*.af.

4     random*.af.


6     (randomized controlled trial or controlled clinical trial) .af. or trial .ti.

7     1 or 2 or 3 or 4 or 5 or 6 or 7

8     limit 7 to human 

Search terms for population 

9      exp Ankle/

10 or ankle

11    9 or 10

12     exp Arthritis/

13     (osteoarthritis or arthritis or arthrosis or osteoarthrosis or (degenerative ˜ (arthr* or disease))).af.

14    12 or 13 or 14

15    11 and 15 

Combining terms 

16    8 and 15 


Appendix 5. CINAHL search strategy

Search terms for design 

1     (MH “Clinical Trials+”)

2     (MH “Random Assignment”)

3     TX (clin$ n25 trial$)

4     TX random$

5     S1 or S2 or S3 or S4

Search terms for population 

6           Osteoarthritis

7           (MH “Osteoarthritis”)

8           TX osteoarthritis

9           TX arthritis

10        TX osteoarthrosis

11        TX degenerative n3 disease

12        Ankle

13        Ankle joint

14        TX ankle

15        S6 or S7 or S8 or S9 or S10 or S11

16        S12 or S13 or S14

17        S15 and S16 

Combining terms 

18     S5 and S17

Appendix 6. PEDro search strategy

1         Osteoarthritis in title or abstract

2         Method: clinical trial

3         Body part: foot or ankle

Combination 1 and 2 and 3 

Appendix 7. AMED search strategy

1    FT=osteoarthritis OR FT=arthritis  OR FT=arthrosis  OR FT=osteoarthrosis

2    FT=ankle OR FT=ankle joint

3    1 and 2 

Contributions of authors

  • Angelique GH Witteveen: draft the protocol, develop a search strategy, search for trials, select which trials to include, extract data from trials, enter data into Review Manager 2013, interpret the analysis, draft the final review, update the review.

  • Cheriel J Hofstad: draft the protocol, develop a search strategy, search for trials, select which trials to include, carry out the analysis

  • Gino MMJ Kerkhoffs: draft the protocol,select which trials to include, interpret the analysis,extract data from trials, draft the final review, update the review.

  • Alfons den Broeder: carry out the analysis, interpret the analysis

  • Inger N. Sierevelt: carry out the analysis

Declarations of interest

None known.